Nadal – a 10-time champion in Rome – suffered a resounding 6-1 6-3 defeat against Hubert Hurkacz on the clay, the Pole producing a polished performance to halt his run in the second round.
The Spaniard has said he will likely call time on his glittering career at the end of the season, having been troubled by hip and abdominal injuries in recent years.
The 37-year-old was also beaten by Jiri Lehecka in the last 16 at the Madrid Open last month, and he acknowledges he is currently some way short of the level required to challenge for a record-extending 15th French Open title.
Speaking after Saturday's defeat, Nadal said: "The time has come to make a decision, in case I might not play Roland-Garros.
"One is to say, 'okay, I am not ready, I am not playing well enough'.
"Another is to accept how I am today and work the proper way to try to be in a different way in two weeks. If I have to say which side I lean towards, it's to try to play it and give my best.
"Physically I have some issues, but probably not enough to say no to playing in the most important event of my tennis career."
The year's second grand slam begins at Roland Garros on May 20, with the men's singles final taking place on June 9.
Nadal has played only once – alongside the now-retired Roger Federer at the Laver Cup – since he was knocked out in the fourth round of the US Open by Frances Tiafoe.
The 36-year-old has won two grand slam titles in 2022, at the Australian Open and the French Open, seeing him sit one clear of Novak Djokovic when it comes to the record amount of major triumphs.
Yet it is Nadal's fellow Spaniard Carlos Alcaraz, some 17 years his junior, who sat top of the world rankings ahead of the Paris Masters and the season-ending ATP Finals in Turin.
Nadal could yet end the year at the summit, but to overtake Alcaraz he would likely need a deep run at the Paris Masters – one of two ATP 1000 tournaments he is yet to win in his illustrious career – and in northern Italy.
However, Nadal, who became a father last month, says he now has a much simpler aim than becoming the best player on the planet.
"To be clear, I understand it's an interesting point because you're talking about fighting for number one, [but] I don't fight any more to be world number one," Nadal said in a press conference on Tuesday, a day ahead of his opening match against Tommy Paul in the French capital.
"I just fight to keep being competitive in every event that I play. It's something I said a long time ago, I will not fight any more to be number one.
"I did in the past. I achieved that goal a couple of times in my career and I have been very, very happy and proud about achieving that. But I am at a moment in my tennis career where I don't fight to be number one.
"I'm just excited to be here. I'm here to try my best and then accept things how they are coming. Hopefully, I will be ready, I'm going to try to be competitive. Let's see. I'm excited about it."
Having dominated the game for so long, Nadal and reigning Paris Masters champion Djokovic find themselves ranked at second and seventh by the ATP respectively.
Nadal and Djokovic are the only players in the top 10 aged over 30, with four of the other eight players aged under 25.
"My feelings are that I am proud of all the things that I was able to still be here in 2022," Nadal said, when asked what it was like to be competing against the next generation of talent.
"It's something that says that I did a lot of things well in my life, not only my tennis career. To hold the passion, to hold the love for the game and fighting spirit.
"I'm proud of that and just hope that I can enjoy the last two events of the year."
With his son not yet a month old, Nadal conceded he is missing home.
"[A] different approach to usual. It has always been difficult to leave home, to be honest," he said.
"It's quite interesting how even after two or three weeks you leave your son at home and [are] not be able to go see him. It's something quite interesting how even after only three weeks of knowing him you start missing him.
"So yeah, a new experience, all changes are difficult in his life, and you need to adapt to it."
Rival Novak Djokovic had already sealed his progress earlier in the day, beating Alejandro Davidovich Fokina in dominant fashion, but Nadal found life hard against Denis Shapovalov.
The Spaniard has already uncharacteristically lost twice on clay courts this season and was heading for a third as he trailed Shapovalov 3-6 0-3.
Even after Nadal recovered to take the second set, he faced two match points in the decider, battling bravely to a vital hold of serve that took the match well beyond the three-hour mark and into a tie-break.
There, Nadal finally took control, running out a 3-6 6-4 7-6 (7-3) winner to reach the last eight and gain some much-needed minutes on the court.
"It's an important victory for me [to] be able to win matches like today, three hours and 27, in the Barcelona final three hours and 38, long matches," said Nadal.
"To be able to win these kinds of matches against young players gives me confidence with my body."
There had been no such test for Djokovic in his 6-2 6-1 rout, although the world number one felt that was in part due to his improving form.
"I thought I played better, at least 20 or 30 per cent better, than I did against [Taylor] Fritz a few days ago," he said. "I am on a good trajectory and hopefully tomorrow will be even better."
Djokovic will face fifth seed Stefanos Tsitsipas next after his straight-sets defeat of Matteo Berrettini.
For Nadal, Alexander Zverev is a similarly tricky opponent having come through three sets against Kei Nishikori.
But not every seed made it through, as Dominic Thiem succumbed to the last remaining home hopeful in Lorenzo Sonego, a dramatic 6-4 6-7 (5-7) 7-6 (7-5) victor.
A meeting with Andrey Rublev is the Italian's reward, while there will be at least one unseeded player in the last four as Federico Delbonis prepares to take on Reilly Opelka.
Nadal displayed an abundance of tactical nous, nullifying the American’s big hitting and service game to emerge the 7-6(6-3) 7-6(7-5) winner.
Along with a 76 percent first-serve rate, Opelka hit more winners with 26 for the match, but the 35-year-old Spaniard was able to grind out points from the baseline with his trademark heavy topspin. As a result, Nadal’s winner/unforced error differential was +14 in comparison to Opelka’s +1.
"He is one of the toughest opponents on tour," Nadal said post-match. "It is very tough to control his weapons with his serve and forehand.
"I think I played my best match of the tournament so far today. I am very pleased with how I was able to win the match, with two difficult tie-breaks. This victory means a lot to me."
The highest ranked player left in the draw, Nadal will now face Nick Kyrgios, who progressed to the quarter-finals after Jannik Sinner withdrew with illness.
Matteo Berrettini made a shock exit, meanwhile, losing 6-3 6-7(5-7) 6-4 to unseeded Serbian Miomir Kecmanovic.
The Italian world number six was put under constant pressure, with Kecmanovic targeting his backhand and hovered the baseline to close the angles on serve.
The 22-year-old’s only other top 10 victory came against Alexander Zverev, also the world number six then, at Cincinnati in 2019. He will now face Taylor Fritz, who defeated Alex de Minaur 3-6 6-4 7-6(7-5).
Also on Wednesday, Grigor Dimitrov edged past John Isner 6-3 7-6(8-6). In his unique style, the Bulgarian 33rd seed came up with the shot of the day, flicking a forehand pass across the visibly stunned Isner.
He will face Andrey Rublev, who defeated Hurbert Hurkacz 7-6(7-5) 6-4. In Wednesday’s other results, Carlos Alcaraz Garfia comfortably defeated Gael Monfils 7-5 6-1, while Cameron Norrie accounted for Jenson Brooksby 6-2 6-4.
World number two Nadal is bidding to win the ATP Masters 1000 tournament for the first time and fought from a set down to triumph 4-6 7-5 6-1 and improve his record against his fellow Spaniard to 7-0.
With Schwartzman having lost his quarter-final against Daniil Medvedev 6-3 6-1 earlier on Friday, Carreno Busta needed to win back-to-back titles in Paris and Sofia to stop the Argentinian taking the last remaining qualifying spot for the season-ending tournament.
He appeared to have a significant chance of keeping his hopes alive when he engineered three break points at the start of the second set, but 20-time grand slam champion Nadal held firm and forced his way into a final-four meeting with Alexander Zverev or Stan Wawrinka.
Nadal came under early pressure on his serve and Carreno Busta took his second chance to break, his impressive groundstrokes proving difficult for his opponent to cope with.
Back-to-back brilliant backhands put him on the brink of going a set and a break up in the first game of the second, but Nadal dug in to hold and began to step through the gears.
Carreno Busta showed impressive resilience to keep the contest on serve in games two and eight, before a wicked forehand down the line forced the match to a decider.
The ninth seed was broken to love in game four of the decider and won just two more points as Nadal surged to victory.
In the other semi-final Medvedev will take on Milos Raonic after the Russian took just 63 minutes to dispatch of Schwartzman.
Things were not as easy for Raonic, who staved off two match points and sent down 25 aces as he overcame Ugo Humbert 6-3 3-6 7-6 (9-7).
The Canadian saved all three of the break points he faced in the third set – and five out of six overall – and closed out the victory with a final ace.
Nadal's fellow Spaniard Feliciano Lopez went close to a major upset as the veteran pushed him all the way, but Nadal came through 4-6 7-6 (7-5) 6-4.
After sweeping to French Open glory last month without dropping a set, Wednesday's match marked Nadal's return to action and it took him two hours and 30 minutes to get the job done.
He sits fourth on the list of players with the most wins in the Open Era, behind Jimmy Connors, Roger Federer and Ivan Lendl.
There were also victories for Alexander Zverev, Diego Schwartzman, Milos Raonic and Alex de Minaur. while Daniil Medvedev went through after opponent Kevin Anderson retired due to injury during a first-set tie-break.
Away from clay, Nadal looks vulnerable in Paris
Nadal was imperious at Roland Garros, roaring through the draw on the way to his 13th French Open title.
Across town, at the Bercy Arena, it has been a different story throughout Nadal's career.
The indoor hard-court event is one he has never won and has often skipped, with this just his eighth appearances in the main draw, and this was almost a brief visit as Lopez made a storming start.
Lopez managed what nobody could at Roland Garros by swiping that first set after a break of serve in the opening game of the match, but 20-time grand slam winner Nadal stepped up his game to reach the last-16 stage and chalk up a landmark win.
The 39-year-old Lopez saved five break points in the second set to earn a tie-break, only for Nadal to edge it and then break serve for the first time at the outset of the decider.
With his hard-fought success, Nadal, 34, extended his head-to-head winning record to 10-4 against Lopez, with their rivalry having begun on an indoor carpet court in Basel back in 2003.
Likely challengers come through
German fourth seed Zverev swept to a 6-2 6-2 win against Serbian Miomir Kecmanovic, while Schwartzman swatted away Richard Gasquet, landing a 7-5 6-3 win over the Frenchman.
There was more disappointment for French hopes as Pierre-Hugues Herbert lost 6-4 6-4 to Canadian Raonic, and Russian Medvedev was embroiled in a battle with Anderson when the South African pulled out of the contest.
Sonego's early exit
Lorenzo Sonego arrived in Paris off the back of a successful week in Vienna, where he knocked out Novak Djokovic in the quarter-finals and went on to finish runner-up to Andrey Rublev.
This week will linger less in the memory for the Italian, who went down 6-3 7-5 to De Minaur.
Nadal, who has won the Madrid Open on five occasions, will face Serbia's Miomir Kecmanovic in the round of 32 on Wednesday, the same day Los Blancos bid to overturn a 4-3 first-leg deficit against Pep Guardiola's team at the Santiago Bernabeu.
The 21-time grand slam winner is known to be an avid supporter of Madrid and was invited to take an "honorary kick-off" before Carlo Ancelotti's team wrapped up their 35th league title with a 4-0 win over Espanyol at the weekend.
Lopez confirmed Nadal's request to Spanish radio network Cadena SER on Tuesday.
"Nadal asked us that when Madrid played the Champions League semi-finals that we not play him," Lopez said.
"He likes to play during the day, so that the ball bounces higher. There are [Spanish] tennis players who are not from Madrid. David Ferrer is not from Madrid. Tommy Robredo and Marc Lopez are from Barcelona, Sergi Bruguera is very much from Barcelona… it's very hard to be an anti-Madridista!"
Real Madrid have been eliminated from each of their previous five Champions League semi-finals when losing the first leg – however, Los Blancos have progressed from two of their last three knockout ties when losing the opening match (the 2015-16 quarter-final against Wolfsburg and this season's last-16 tie against Paris Saint-Germain).
Madrid have won the European Cup/Champions League on a record 13 occasions, also finishing as runners-up three times, and Nadal will hope to have a good view if Los Blancos seal a 17th final appearance on Wednesday.
World number two Nadal, chasing a record-extending sixth title on home soil, advanced 6-3 6-3 in a time of one hour and two minutes on Thursday.
Popyrin, playing in his first last-16 match at a Masters 1000 event, broke Nadal in the sixth game of the opening set but the Spaniard otherwise looked comfortable.
Nadal converted four of his six break points to advance through to the last eight for a 15th time, where Alexander Zverev awaits.
"It was difficult," Nadal said in his on-court interview. "The court today was slippery, it was very fast, very dry conditions. The ball was flying a lot. The beginning was super tough.
"He was hitting every ball and hitting the spots. I'm happy with the victory. It was an important victory, he came here playing well. Every match is tough."
Zverev, who won the competition in 2018, beat British number one Dan Evans 6-3 7-6 (7-3) to set up a meeting with Nadal
However, second and fourth seeds Medvedev and Tsitsipas saw their participation come to an end at the hands of Cristian Garin and Casper Ruud respectively.
Medvedev, who is still yet to reach the quarters in Madrid, lost the only break of serve in the third game of the opening set but recovered by taking the second set in a tie-break.
Garin dominated the deciding set, the world number 25 breaking Medvedev twice and, after a short delay to fix a broken net, advanced 6-4 6-7 (7-2) 6-1.
Tsitsipas, who held championship point against Nadal in the Barcelona Open final, failed to break Ruud on a single occasion as he fell 7-6 (7-4) 6-4.
Alexander Bublik is next up for Ruud after beating Aslan Karatsev 6-4 6-3, while Matteo Berrettini - 7-6 (7-4) 6-4 winner against Federico Delbonis - will meet Garin.
Also vying for a place in the semi-finals are John Isner and Dominic Thiem, who are set to face off after beating sixth seed Andrey Rublev and Alex de Minaur respectively.
Rising star Sinner gave Nadal a stern test, but the veteran emerged triumphant with a 7-5 6-4 triumph in two hours and 12 minutes.
Nadal will face Denis Shapovalov – who also beat an Italian in the shape of Stefano Travaglia – in the last 16.
The hard-fought victory is a welcome one for Nadal after he lost to Alexander Zverev in the Madrid Open quarter-finals last time out.
However, there was a big star who fell with world number two Medvedev, who continues to struggle on clay, eliminated by his compatriot Aslan Karatsev.
Karatsev impressively triumphed 6-2 6-4 in 78 minutes, winning 26 of his 29 first-serve points and not being broken in the match.
"I'm super happy," said Karatsev, who also beat world number one Novak Djokovic last month and will face Reilly Opelka next.
"It was a really tough match. Against Medvedev you never know, he's a big server. It's tough to return, but I managed it well."
Dominic Thiem almost went the same way as Medvedev, coming within two points of going out in his first match in Rome, which has also happened in his previous two appearances.
However, the Austrian battled back to defeat Marton Fucsovics 3-6 7-6 (7-5) 6-0 in a match lasting two hours and 33 minutes, booking a last-16 clash with Lorenzo Sonego.
"It was such a close match, especially in the second set,” said Thiem, a semi-finalist in Madrid last week.
"I knew he'd be a super-tough opponent, particularly coming from different conditions in Madrid. I was fighting all the match and stayed in there.
"At the end, I got the reward for fighting. I had difficulties with my timing and my serve.
"I have to hurt my opponent more with my shots. I still won a great match and I will try to improve."
There were smoother victories for Madrid champion Zverev and Stefanos Tsitsipas.
Zverev cruised past qualifier Hugo Dellien in a 6-2 6-2 success, while Tsitsipas saw off Marin Cilic 7-5 6-2.
Andrey Rublev defeated Jan-Lennard Struff in three sets, while Matteo Berrettini also progressed, beating John Millman in straight sets to book a clash with Tsitsipas which looks like the pick of the last-16 draw.
The world number four's bid for an 11th title in Rome got off to a strong start on Wednesday as he saw off big-serving Isner 6-3 6-1 in a time of 76 minutes.
Isner twice missed the chance to break Nadal in the seventh game of the opening set and the Spaniard took control from that point on in the second-round match.
Nadal, who has won this tournament in three of the past four years, identified that hold of serve as a key point in the contest.
"The beginning of the match was not good for me," he said in his on-court interview. "He had some chances on the return and had two break points.
"He had two not difficult balls so I was in his hands at that moment. I was lucky that he missed those shots and then I was able to break.
"Then the match changed, of course. With the first set on the board, and having the break in the first game of the second set, everything changed."
Nadal will now face Shapovalov in a repeat of last year's last-16 encounter, which the record 21-time grand slam winner edged in three sets.
He recovered from a set down and saved two match points before beating the Canadian 3-6 6-4 7-6 (7-3) en route to lifting the title in the Italian capital.
And Nadal, who was beaten by Carlos Alcaraz on clay in last week's Madrid Open quarter-final, is not expecting an easy task this time around.
"Last year was a joke, the match that I saved here against him," said Nadal of his next opponent. "I was super lucky. I know how dangerous he is, I need to play well.
"I need to play better than today, but after a while without being on court it is another victory and I have the chance again to play against one of the best players in the world.
"I need to build things again after a tough stoppage and that's what I am trying now. I just need to stay with the right attitude, and let's see if I am able to make that happen."
Alexander Zverev also booked his place in the last 16 on Wednesday thanks to a 7-6 (8-6) 6-3 victory over Sebastian Baez.
Last week's Madrid Open runner-up was given a tough time of things by in-form Baez, but ultimately came through unscathed to stay on course for more silverware.
Playing his first match since winning the Mexican Open on February 29 before the sport was shut down, Nadal defeated his fellow Spaniard 6-1 6-1 in just 73 minutes.
It was an emphatic return to action against Carreno Busta, who took Alexander Zverev to five sets after a run to the US Open semi-finals last week.
World number two Nadal will meet either Milos Raonic or Dusan Lajovic in the last 16.
Both players survived break-point opportunities in their opening service games, before Nadal reeled off five straight games to win the opener.
Carreno Busta stopped the rot with a hold to open the second set but was otherwise powerless to stop Nadal, who won every game from there.
Despite a first-serve percentage of just 49, Nadal only faced one break point in the contest as he beat Carreno Busta for the sixth straight meeting.
Nadal's win on Wednesday came after Novak Djokovic showed little sign of being affected by his US Open default in a 6-3 6-2 win over Salvatore Caruso.
The standout result of the day saw teenage home hope Jannik Sinner record a superb win over third seed Stefanos Tsitsipas, triumphing 6-1 6-7 (9-11) 6-2 for just the second top-10 win of his career.
Matteo Berrettini was another Italian to win in Rome as he beat Federico Coria in straight sets, while Marin Cilic defeated sixth seed David Goffin 6-2 6-2.
Nadal, 34, has won the competition more times than anyone else in its history and looked in good shape as he returned to the court for the first time since losing to Stefano Tsitsipas in the Australian Open quarter-finals on February 17.
He needed just 81 minutes to get past the Argentinian qualifier 6-1 6-2 as he improved his record in the tournament to 72-5, breaking Delbonis' serve five times and only dropping his own once.
He is not getting carried away, however, with Grigor Dimitrov likely to provide a sterner test in the next round after beating Jeremy Chardy 7-6 (7-3) 6-4.
"It was solid match, I think. Of course, a very positive result. He's a good player on clay. [It was a] positive start for me," Nadal said in his post-match interview.
"I think I just really played a solid match. Nothing unbelievable, but nothing wrong. Just a solid match, a positive start. I think I did what I had to do."
On Dimitrov, Nadal added: "We've had some great matches. In Melbourne, of course... we played another great match in Beijing, another one in Shanghai. He's a good friend, a good guy, and a great player. It's going to be a tough test in my second round.
"It's going to be his third. I need to be ready for it. I hope to be ready for it. I am just excited to play a tough match very early in the tournament."
A little earlier in the day, world number one Djokovic was in a similarly unforgiving mood as he overcame the potentially tricky obstacle of Jannik Sinner, the Serbian and two-time Monte Carlo champion winning 6-4 6-2.
Like Nadal, Djokovic was back in action for the first time since the Australian Open – which he won – and appeared fresh as he gave the promising young Italian something of a lesson in game management, reaching 10 matches unbeaten at the start of a season for the sixth time.
"It feels great [to be back and] also playing in Monaco, where I reside," Djokovic said. "I have used this club as a training base for almost 15 years, so it feels like playing at home."
Despite the rather commanding nature of his win, Djokovic was keen to pay tribute to the 19-year-old Sinner, adding: "It was a very good encounter. I thought it was a great first match [and] a big challenge for me. Jannik is in form. He played the final [in] Miami and has been playing well. I just hung in there today and managed to find the right shots and the right game at the right time.
"He has got a lot of talent and he has proven that he is the future of our sport. Actually, he is already the present of our sport. He played a final [in an] ATP Masters 1000 [tournament] already. He is making big strides in professional tennis."
Dan Evans awaits Djokovic after an impressive 6-4 6-1 win over Miami champion Hubert Hurkacz, while Alexander Zverez and Andrey Rublev – the fifth and sixth seeds – moved into the next round with respective straight-set victories over Lorenzo Sonego and Salvatore Caruso.
There were mixed fortunes for the other two top-10 seeds in action on Wednesday, as Pablo Carreno-Busta defeated Karen Khachanov 6-2 6-3, but Diego Schwartzman was sent packing by Casper Ruud, the Norwegian winning 6-3 6-3.
Nadal has been sidelined since suffering a cracked rib during the Indian Wells Masters last month.
The 21-time grand slam champion on Tuesday revealed he has decided to make his ATP Tour comeback at the Caja Magica.
He posted on social media: "Despite preparation being difficult, I really want to play at home since the opportunities are few.
"[I want] To try to do it in the best possible way. See you in Madrid."
Taylor Fritz consigned Nadal, a five-time champion at the Madrid Open, to his first defeat of the year in the final at Indian Wells.
The Australian Open champion was visibly struggling to breath during that match after sustaining the injury during a semi-final victory over fellow Spaniard and heir apparent Carlos Alcaraz. The 35-year-old's 2022 record so far stands at 20-1.
Nadal's return is set to make his comeback just three weeks before he will be hoping to start his bid to win a 14th French Open title at Roland Garros.
The world number two moved into the last 16 with a 6-1 6-2 victory on Wednesday.
After being knocked out of the Monte Carlo Masters by Andrey Rublev in the last eight, Nadal bounced back to win the Barcelona Open last month and continued his momentum in this round-of-32 clash.
As wildcard Alcaraz turned 18, the spectators sang happy birthday to him but he could not mark the occasion with a famous result against his idol, with Nadal broken just once on his way to a 78-minute victory.
Five-time tournament winner Nadal converted five of his seven break points in a ruthless showing, with Real Madrid greats Iker Casillas and Raul in the crowd to watch him.
Nadal will play Alexei Popyrin, a straight-sets winner against rising star Jannik Sinner, in the next round.
Elsewhere, second seed Daniil Medvedev came from behind to defeat home hope Alejandro Davidovich Fokina 4-6 6-4 6-2. It was his first win in seven ATP Tour matches on clay.
"I am happy with the win," said the Russian.
"The first set wasn't easy and I thought it was going to be where I had another 25 break points and I wouldn't win.
"I finally played quite well and did well in the third set. Madrid is a little faster than other clay tournaments, so it is better for my game."
The win means Medvedev has an 18-3 record this season and faces Chile's Cristian Garin next.
Medvedev's compatriot Aslan Karatsev beat Diego Schwartzman 2-6 6-4 6-1, having also defeated the French Open semi-finalist at the Australian Open this year.
In-form Karatsev will face Alexander Bublik next after his fourth top-10 win of the year.
Fifth seed Alexander Zverev said he was "clinical" in dispatching Kei Nishikori 6-3 6-2 in just 74 minutes, while fourth seed Stefanos Tsitsipas will play Benoit Paire later on Wednesday.
Nadal, a five-time champion at this event, was a break up in the first set of his 15th quarter-final at Caja Magica but lost 6-4 6-4 in an hour and 44 minutes.
Zverev had won the previous two meetings with Nadal, both on indoor hard courts, after losing five consecutive matches against the 20-time major champion including a 6-1 6-1 rout in Monte Carlo in their first clay contest four years ago.
The world number six has five clay-court titles to his name, including this event in 2018, but defeating 13-time French Open champion Nadal on his favourite surface in front of a home crowd ranks among Zverev's finest achievements.
It looked as though Nadal was assuming control when he broke to love to lead 4-2 in the first set, but Zverev responded with a break back at the first time of asking.
The German had spoken of the Madrid courts playing faster than other clay events and the conditions certainly seemed to suit his fearless approach as Nadal struggled to deal with his crosscourt backhand.
He won the next three games to clinch a first set in which he lost just four of 16 points behind his first serve.
While Zverev looked increasingly confident, mixing up his shot depth and frequently coming to the net, Nadal cut an unusually frustrated figure even as he showed customary battling qualities to ward off a break point at 1-1.
However, more powerful hitting from Zverev saw him break to lead 4-2, and although he missed two chances for a double break, he closed out the match with minimal fuss.
"Definitely one of the biggest wins of my career," Zverev, who will face Dominic Thiem in the semi-finals, told Amazon Prime Sport. "Beating Rafa on clay is one of the toughest things to do in our sport."
Nadal went into the meeting with a 73-5 record at the event but Russian Rublev was in inspired form to stun his Spanish opponent.
The 11-time champion looked set to complete a trademark comeback after taking a 74-minute second set, yet Rublev held firm in the decider to claim a memorable victory after two hours and 33 minutes on court.
"I cannot imagine being in the situation of Rafa, knowing that you are the best player on clay and you have that pressure every time," Rublev said, according to the ATP Tour website.
"I think for him it must be incredibly tough every time. I am in shock [with] the way he is playing under this pressure and that is why he is a legend."
Rublev will face Casper Ruud in Saturday's semi-final after he overcame defending champion Fabio Fognini 6-4 6-3.
Dan Evans followed up his superb victory over Novak Djokovic on Thursday with a slender win over David Goffin to reach his first Masters 1000 semi-final.
World number 33 Evans, who had come into the tournament having lost his previous 10 matches on clay, overcame Goffin 5-7 6-3 6-4 in two hours and 42 minutes.
"I am proud of how I came back today, especially with what happened in the first set," he said after the match.
"I felt my concentration wasn't great and I am really happy with coming through. Yesterday would not have been worth it with a bad performance today."
Evans will face Stefanos Tsitsipas, who progressed when opponent Alejandro Davidovich Fokina retired injured in their quarter-final.
Spaniard Davidovich Fokina did not return for the second set after earlier receiving treatment during the first, which Tsitsipas won 7-5.
'King of Clay' Nadal fell to a 1-6 7-5 6-2 defeat to Shapovalov in the third round in Rome, with the Canadian surging to victory after winning 12 straight points from 2-2 in the deciding set.
The legendary Spaniard stormed through the first set thanks to a series of brilliant returns, but his opponent dominated at the net in the second to take the match the distance.
Shapovalov then flipped the narrative on its head by winning 14 of a possible 22 return points to set up a quarter-final meeting with Casper Ruud, who beat Jenson Brooksby 6-3 6-4.
Djokovic is one win away from retaining his status as world number one after taking just 75 minutes to see off three-time grand slam winner Stan Wawrinka 6-2 6-2.
After a lengthy spell out injured, Wawrinka ended a 15-month wait for an ATP Tour victory at Foro Italico before the Serbian brought his run to an end.
"It is great to see Stan back and winning. He won two tough matches. You can see he is still not physically where he wants to be. But, nevertheless, he is Stan Wawrinka and he can hurt you if you give him time," Djokovic said.
"I managed to do well from the beginning. I really moved him around the court and held my serve comfortably except for that loss of my serve in the second set."
Felix Auger-Aliassime stands between Djokovic and the number one spot after overcoming lucky loser Marcos Giron 6-3 6-2.
In the other half of the draw, Stefanos Tsitsipas and Jannik Sinner will play out an entertaining quarter-final after they beat Karen Khachano and Filip Krajinovic respectively.
Alexander Zverev, the defeated finalist in Madrid last week, beat Alex De Minaur 6-3 7-6 (7-5) and will battle Cristian Garin for a place in the final four.
The 20-time major champion played at the Mubadala Tennis Championship in Abu Dhabi last weekend and declared his mission a success despite consecutive defeats on his return from a foot injury.
Indeed, Nadal had only competed in two matches since losing to Novak Djokovic in the French Open semi-finals in June before testing his long-term foot problem against Andy Murray and most recently Denis Shapovalov.
However, the 35-year-old's plans to feature in the Melbourne ATP 250 ahead of the Australian Open in early January have suffered a setback after he tested positive for COVID-19 upon landing in his home country on Monday.
Nadal revealed the news on Twitter as he posted: "I wanted to announce that on my return home after playing the Abu Dhabi tournament, I have tested positive for COVID in the PCR test that was performed on me when I arrived in Spain.
"Both in Kuwait and Abu Dhabi we passed controls every two days and all were negative, the last being on Friday and having the results on Saturday.
"I am having some unpleasant moments but I hope that I will improve little by little. I am now homebound and have reported the result to those who have been in contact with me.
"As a consequence of the situation, I have to have total flexibility with my calendar and I will analyse my options. I will keep you informed of any decisions about my future tournaments!"
Nadal was eyeing the Australian Open, which starts on January 17, as his first major comeback, though he earlier admitted his entry was not guaranteed as he evaluated his foot injury and physical fitness.
"I cannot guarantee Australia one hundred per cent, because I need to go home and see how the body responds after these days," Nadal told reporters on Saturday.
"I have time to make a decision. At this point in my career, I need to go day by day, study each movement well.
"I have been able to show a competitive level against good players even without being in perfect condition. There are things to improve but looking at things with perspective it has been a positive tournament [in Abu Dhabi].
"The main objective is to be healthy enough to do the things that I need to do and aspire to the objectives that I have always had. The illusion and passion continue to exist."
The ATP Tour event in Melbourne, which would be Nadal's first such tournament since August, is due to start on January 3.
Djokovic continued his stellar year by claiming the title in Rome thanks to a 7-5 6-3 win over Diego Schwartzman in the final on Monday.
The Serbian won his 36th ATP 1000 title, moving him ahead of Nadal into the outright lead, in the ideal preparation for the French Open starting on Sunday.
While Nadal was beaten by Schwartzman in the last eight in Rome, Djokovic said the 12-time French Open champion still deserved favouritism at Roland Garros.
"It's Nadal. Even though he lost this week I still think, and a lot of people will agree, he is the number one favourite," Djokovic told a news conference.
"The record that he has there, the history of his results, you just can't put anyone in front of him. But Diego showed Nadal is beatable on clay.
"The conditions that they played on, heavy clay, not much bounce, humid, night session, we are going to have that as well in Paris. Night session, under the lights, a little bit less bounce, I am pretty sure he does not prefer that to high bounce. I know he likes the high bounce, he likes hot and fast and warm conditions where he can use his spin a lot.
"Let's see. It's going to be interesting. Even though he's the number one favourite there are players who can win against him there.
"It's obviously best of five. You've got to be really fit to be able to achieve that."
A 17-time grand slam champion, Djokovic won the French Open in 2016, while he has lost three finals at the tournament, including two to Nadal.
But with the event rescheduled from a May start to September, Djokovic hopes the cooler weather will suit him in Paris.
"I cannot hope for Rafa not being in the final. I can hope for myself being in the finals and fighting for the trophy," he said.
"That's probably the player who has the highest chance of being in a final in the French Open and any tournament for that matter. If there is one tournament, that is Roland Garros and that's Rafa that you would bet on. But conditions will be different.
"I think I experienced something that might be the case in terms of conditions in Paris. Little bit of rain, wet court, clay, not much of a bounce, a bit cold. That's what I think people have been talking about from the Paris weather standpoint. I'm fine with those conditions."
Nadal needed three sets to secure the 1,000th ATP Tour-level victory of his career at the expense of Feliciano Lopez on Wednesday.
The top seed followed that up with a 6-1 7-6 (7-3) defeat of world number 61 Thompson in Bercy, reaching the quarter-finals of the tournament for an eighth time out of eight.
Nadal lost just 12 points behind his serve as Thompson failed to break the 20-time grand slam champion in the first meeting between the two on Thursday.
Ninth seed Carreno Busta stands in the way of Nadal and a place in the last four, as one of the all-time greats attempts to win the tournament for the first time.
Nadal was up against it in a battle with veteran Lopez before sealing a landmark win, but there was no slow start from the legendary left-hander in his third-round contest.
He held to love in the first game and in the fifth, then took a 5-1 lead with a deft volley at the net after drilling a rasping return and an inside-out forehand to Thompson's left.
The world number two wrapped up the set in only 32 minutes by winning a fifth consecutive game, but it was a different story in the second as Australian Thompson warmed to the task.
Thompson threw down his racket and was shaking his head after failing to win a set point before Nadal took it to a tie-break, which he won with a combination of thunderous winners and errors from his opponent.
