Several quarter-finals were squeezed into Saturday's schedule alongside evening semi-finals following Friday's ranout, forcing Alcaraz to play twice along with Diego Schwartzman who also progressed to Sunday's decider.
Alcaraz first defeated top seed and 2021 Wimbledon finalist Berrettini in three sets, triumphing 6-2 2-6 6-2 in two hours and two minutes.
The 18-year-old Spanish seventh seed, who reached last year's US Open quarter-finals, backed that up with a straight-sets win over Fognini, 6-2 7-5.
"It means a lot to me," Alcaraz said post-match. "I surprised myself to be able to win two matches in a row in the same day. It's tough to win one match, two is even tougher."
Third seed Schwartzman got past fellow Argentine Francisco Cerundolo 7-6 (7-4) 6-3 in a two-hour-and-two-minute semi-final, having won through earlier in the day 7-6 (7-3) 4-6 6-4 against Pablo Andujar.
The top two seeds will meet in the Delray Beach Open final in Florida after wins by Cameron Norrie and Reilly Opelka on Saturday.
First seed Norrie got past American fourth seed Tommy Paul 6-3 6-3 in one hour and 16 minutes. Norrie had endured a slow start to the calendar year, but will now play for a third ATP Tour title.
Second seed Opelka had a tougher outing, needing three hours to overcome John Millman 7-6 (10-8) 6-7 (3-7) 7-6 (7-4). In a match which only saw two breaks of serve,
Opelka, who won last week's Dallas Open title, sent down 16 aces and won 82 per cent of his first serve.
The 18-year-old became the youngest winner of an ATP 500 event since the creation of the category in 2009, clinching a 6-4 6-2 victory in one hour and 26 minutes.
Alcaraz, set to climb into the world's top 20 for the first time, captured his second tour-level title after triumphing at last year's Croatia Open.
The Spaniard won five out of six break points, including a crucial one at 4-4 on his way to taking the opening set.
Third seed Schwartzman – champion in Rio in 2018 – was appearing in his second successive final, having reached the showpiece in Buenos Aires last week.
But the Argentinian was unable to compete with the powerful seventh seed on clay, the surface on which Alcaraz could do major damage in the coming years.
Meanwhile, Cameron Norrie landed his third ATP Tour title after beating Reilly Opelka 7-6 (7-1) 7-6 (7-4) in the Delray Beach Open showpiece.
Top seed Norrie had endured a torrid start to the 2022 season, which began for him with four successive defeats.
Meanwhile, Opelka was seeking a second title in as many weeks following his triumph at the Dallas Open.
The American had won six out of six tie-breaks on his way to victory in Dallas, and a further four this week.
But despite the big-serving second seed hitting 25 aces against Norrie, taking his tournament tally to 81, and 46 winners, a total of 33 unforced errors proved costly.
Although he was denied all five opportunities to break as both sets went to a tie-break, Norrie's service game remained solid throughout and just seven unforced errors underlined his strong performance.
Murray won the opening set 6-2 before eighth seed Goffin, who had been receiving treatment on his knee, determined he could no longer continue.
It is the first time the 34-year-old Murray has reached a semi-final on the ATP Tour since winning the European Open title in October 2019.
Though not ideal circumstances, Murray will at least be glad of the extra rest after his three-hour encounter with world number 23 Nikoloz Basilashvili in the second round. The Scot has also been drawn to play Basilashvili in the first round of the Australian Open.
Murray will face Reilly Opelka in the last four in Sydney after the American beat compatriot Brandon Nakashima 7-6 (7-4) 6-2 to advance.
Top seed Aslan Karatsev was made to work for his win against Italy's Lorenzo Sonego but secured a 6-3 3-6 6-2 victory to book his semi-final place against Briton Dan Evans, who defeated American Maxime Cressy 6-4 7-6 (7-5). Cressy reached the final of the Melbourne Summer Set tournament last week.
At the Adelaide International 2 event, third seed Karen Khachanov tumbled out after losing in straight sets to Arthur Rinderknech, the Frenchman coming through a 7-6 (9-7) 7-5 winner.
Rinderknech will face compatriot Corentin Moutet in the semi-finals after the qualifier overcame Thiago Monteiro 6-4 6-4.
Fourth seed Marin Cilic battled to beat American Tommy Paul 6-4 2-6 6-3, and a test awaits against Thanasi Kokkinakis who defeated fellow Australian Aleksandar Vukic 6-7 (5-7) 6-3 6-2.
Murray won 6-7 (6-8) 6-4 6-4 against his American opponent, with fourth seed and world number 25 Opelka undone by the British wildcard.
Three years have passed since Murray came to Australia and indicated he was close to retirement due to hip trouble.
There have been highs and lows since then as the three-time grand slam winner has fought to resuscitate his career. His lone ATP final appearance since that point came at the 2019 European Open in Antwerp, where he beat Stan Wawrinka to land a surprise title.
Now he is back in another title match, for what will be just his fourth final on the main tour since the end of the 2016 season, when he reached world number one status.
Opelka is renowned as a big server and duly sent down 20 aces and four double faults, but Murray showed he can compete on that front too with 16 aces and no doubles.
The Scot also won an impressive 88 per cent of points when he landed his first ball in court, and his serve was not broken at any point.
Murray was awaiting the winner of the second semi-final between his fellow Briton Dan Evans and Russian Aslan Karatsev.
Five-time Australian Open runner-up Murray has been drawn to face Georgian Nikoloz Basilashvili in the first round of the grand slam at Melbourne Park next week. He beat 23rd-ranked Basilashvili in round two in Sydney.
World number one Djokovic came from a set down overnight to beat Stefanos Tsitsipas 4-6 7-5 7-5 early on Saturday, before returning to the court to face Italian Lorenzo Sonego in the evening.
The Rome crowd raucously rallied behind Sonego, who beat Andrey Rublev earlier in the day, and the 26-year-old rose to the challenge but eventually fell to a 6-3 6-7 (5-7) 6-2 defeat.
Djokovic had match points before serving for it at 6-5 in the second set, yet it was to prove a stirring game as the noisy home crowd encouraged Sonego, who snatched a gutsy break. The tie-break looked set to be wholly one-sided when Djokovic raced 3-0 ahead, but it was soon back on serve, partisan spectators at the Foro Italico roaring in delight at a double fault from the Serbian.
From 4-2 behind, Sonego surged to 6-4 ahead in the tie-break. He failed to convert a first set point when ripping a forehand into the net, but the set was his when Djokovic sent a backhand service return long.
Sonego then had 0-40 against the Djokovic serve at the start of the decider, but he could not force the break, and the top seed gained strength from that escape, eventually cruising to victory.
Five-time Rome champion Djokovic said on Amazon Prime: "I bounced back very well after the second set. Maybe if he started with a break up in the third, things would look differently. I also had my chances and I only had myself to blame for not closing the match in straight sets.
"But he's a quality player, very dynamic, it's not easy to play against him and obviously he had the crowd behind him. It was an electric atmosphere. In the end I managed to close out the match really well."
Looking ahead to tackling Nadal, Djokovic said: "I need to recover. Hopefully I'll have fresh legs because that's what I definitely will need and it's necessary to have a chance against Rafa. He also had some tough matches [this week] and hopefully I'll be fresh and I'll give it all."
While Djokovic and Sonego thrashed away into the night, nine-time champion Nadal had no such workload issues on Saturday.
Nadal beat Alexander Zverev on Friday to set up a semi-final against American Reilly Opelka, and the Spaniard snatched a 6-4 6-4 win from that contest to reach the title match.
Reigning champion Djokovic, who is seeking a sixth triumph in Rome, struggled to get going against Tsitsipas and trails 6-4 2-1 ahead of the scheduled resumption of play on Saturday.
The top seed lost serve in the first game and continued to make some uncharacteristic errors that saw him trail 4-1 at one point.
While Djokovic did earn a first break in the sixth game, Tsitsipas stood firm to take the opening set and was in total control when again breaking his opponent early in the next set.
However, soon after the Greek had opened up a 2-1 advantage, the worsening conditions led to a pause in proceedings and organisers were eventually forced to bring the day's play to an end.
Djokovic, who converted just one of his six break point opportunities, will return to the court on Saturday and will need to improve if he is to join Rafael Nadal in the final four.
Nadal exacted some revenge on Alexander Zverev earlier on Friday to reach the semi-finals for a 12th time.
The Spaniard lost to Zverev at the same stage of the Madrid Open seven days ago but responded to questions over his form by easing through this latest encounter.
Nadal, who saved two match points before beating Denis Shapovalov on Thursday, raced 4-0 ahead in the first set against Zverev and had little trouble seeing the job through.
Aiming for a record-extending 10th title in the Italian capital, Nadal saved all eight break points he faced in the second set to advance 6-3 6-4 in two hours.
"I played more solid than Madrid. Conditions are different," he said in his post-match interview. "Here the conditions are a little more normal. I was able to control a little bit more."
"I'm happy. I played a very solid match with not many mistakes, playing the way that I have to. It's an important victory for me against a great player."
Nadal will face Reilly Opelka for a place in the final, the American beating qualifier Federico Delbonis 7-5 7-6 (7-2) to reach his first ATP Masters 1000 semi-final.
Opelka entered the tournament on a six-game losing streak, but he kept his good run going in Rome by earning the only break of the opening set in the 12th game.
Both players held throughout the second set and it was big-serving Opelka who prevailed 7-2 in the tie-break.
The day's other quarter-final between Lorenzo Sonego and Andrey Rublev also fell victim to the bad weather and will get under way on Saturday.
Fifth seed Paul started the day off with a straightforward 6-3 6-3 win against South Korea's Kwon Soon-woo thanks to a clear advantage with his serving. He won 73 per cent (36-of-49) of his points on serve, while Kwon could only muster 53 per cent (34-of-64).
Paul will meet Belarus' Ilya Ivashka in the quarter-finals after he successfully navigated the challenge of America's Steve Johnson 4-6 6-2 6-4 after Johnson was a late injury replacement for top overall seed Reilly Opelka.
Ivashka is now 6-3 in his nine matches since the French Open, with his only losses against top-five talents Stefano Tsitsipas and twice against Daniil Medvedev.
Fourth seed Tiafoe was impressive against Japan's Taro Daniel, creating eight total break point opportunities, and capitalising on three.
Tiafoe will play Nakashima in the quarter-finals, with the American surviving a tough first set tiebreaker to eventually defeat Australia's John Millman 7-6 (10-8) 6-4.
In a closely contested match, Nakashima avoided getting into many sticky situations, saving the only break point he faced.
Fritz, who reached last week's Los Cabos Open semi-finals and is currently ranked 36th in the world, edged out Opelka 7-6 (7-5) 6-7 (3-7) 7-6 (7-4) in just under three hours.
The pair sent down a combined 48 aces, with Fritz claiming 25 of them, with all sets going to tiebreakers, with no breaks of serve.
Third seed Cameron Norrie was bundled out by Finnish world number 78 Emil Ruusuvuori in straight sets.
Norrie, who won last week's Los Cabos Open for his maiden ATP Tour title, was beaten 7-6 (7-1) 6-3 by the Finn.
Ruusuvuori will take on teenager Brandon Nakashima in the semi-finals, after the American – who was runner-up to Norrie in Los Cabos - beat Jordan Thompson 7-6 (7-5) 7-5.
Sixth seed John Isner sent down 30 aces as he got past Australian qualifier Chris O'Connell 7-6 (7-5) 6-7 (3-7) 6-4.
The three-time grand slam winner made his tour return last month after requiring two surgeries on a left foot injury, but rallied after losing his first set against Opelka to secure a memorable 3-6 7-5 6-2 first-round victory.
Speaking after booking a second-round meeting with Laslo Djere, who beat Borna Coric 6-2 6-7 (3-7) 6-2, Wawrinka said his desire to play at the top level never left him, despite his injury woes.
"I think in general I was feeling good on the court, physically I was feeling great," he said. "For sure, when you don't win a match in more than a year, you start to think about it more than you should and not focus on the right things.
"In general, I think it was a great match, a great battle. I stayed positive. I started to feel much better with my tennis by the end of the second set, and in the third set. I'm really happy with this victory.
"After two surgeries, at my age I could easily have stopped playing because my career is way better than what I expected when I was young.
"But I still have this fire in me. I still believe that I can play great tennis. I still believe that I make some big results, maybe not now, but in a few months."
Fellow former grand slam champion Dominic Thiem, who also returned from a long injury-enforced absence last month, fared less well, going down in straight sets to Fabio Fognini.
Having lost to Andy Murray at the Madrid Open last time out, 2020 US Open winner Thiem is still chasing his first victory of the year after losing 6-4 7-6 (7-5) to the 34-year-old Italian.
Elsewhere, 13th seed Denis Shapovalov edged an epic three-hour contest against Italy's Lorenzo Sonego 7-6 (7-5) 3-6 6-3, responding after being handed a game penalty for shouting expletives at a partisan crowd in Rome during the second set.
The frustrated Canadian was heard to tell spectators: "Shut the f*** up" when being booed after complaining about a second serve being called out by the umpire, but eventually regained his composure to claim a three-set win.
Shapovalov will face Georgia's world number 25 Nikoloz Basilashvili in the second round after he overcame Daniel Evans 7-6 (7-2) 6-2, while the only other seed to play on Monday, Spain's Pablo Carreno Busta, cruised to a 6-3 6-2 victory over Federico Delbonis.
The trio join Denis Shapovalov, Felix Auger-Aliassime and Diego Schwartzman for the team event which runs from September 24-26 at TD Garden in Boston.
Laver Cup newcomer Opelka rose to a career-high world number 23 ranking en route to his first ATP Masters 1000 final in Toronto and defeated world number three Stefanos Tsitsipas, who will play for Bjorn Borg's Team Europe.
Isner, who has featured for Team World since the inaugural event in 2017, reached the semi-finals in Toronto and claimed his 16th ATP Tour title in Atlanta at the start of August.
He described the Laver Cup as "a highlight of my year", adding: "To be on a team with guys we're normally competing against is so different and so much fun. We come together so well as a group, the chemistry is awesome and it's such a great environment to be part of."
Australian firebrand Kyrgios is a striking inclusion in Team World's roster, while Team Europe will be without their big three: Roger Federer, Rafael Nadal and Novak Djokovic.
Federer and Dominic Thiem were expected to take part in this year's event, though both were forced to withdraw with injuries.
However, Borg's men still boast six of the world's top 11. World number two Daniil Medvedev leads the line-up, with Tsitsipas and Tokyo Olympics gold medallist Alexander Zverev for company.
Casper Ruud, who collected a 14th win in his last 15 completed matches on tour when he beat Opelka on Wednesday, will feature, while Andrey Rublev and Wimbledon finalist Matteo Berrettini complete the six-man team.
Team Europe have landed the title in each of the three editions of the tournament so far, with Prague, Chicago and Geneva having served as hosts.
Before Tuesday's victory over Mackenzie McDonald, Kyrgios had not played on clay since his infamous meltdown against Casper Ruud at the Rome Masters in 2019, where he threw a chair across the court and walked off during a change of ends.
The 26-year-old Australian wild card's serve kept him in relative control, saving all six break points he faced in the 70-minute match, as well as serving 10 aces and winning 88 per cent of points on his first serve.
"I had to be locked in today and I knew that I had to serve well," Kyrgios said post-match. "It's probably one of the better matches I've played on clay in my career, so I'm pretty happy with the way I came out here today, just put my head down and went to work.
"I've been serving really well, so I just wanted to keep to good habits."
The world number 94 will now face Michael Mmoh, who defeated Sam Querrey 6-2 6-4.
Meanwhile, third seed Reilly Opelka did it relatively tougher in the other all-American clash on Wednesday, coming back from a set down to defeat Mitchell Kreuger 3-6 6-2 6-4.
Opelka came into the match having lost just 13 service games in 19 matches this season, but was broken twice in the opening set against Krueger. The world number 18 has been dealing with a right shoulder injury that forced him to retire at the Miami Open against Francisco Cerundolo.
The 24-year-old still managed 15 aces for the match, including a big serve out wide in the Ad court on match point.
"He played well, I think he came out swinging," Opelka said afterwards. "I think he was free, I wasn't. It's a different situation.
"It was a good opportunity for him to play free and get a win and I'm a guy who hasn't always been the most consistent, especially changing surfaces, so I think it was a good win."
He will face Gijs Brouwer, who progressed past J.J. Wolf with a 6-1 6-1 win.
Opening-day honours went to Bjorn Borg's Team Europe at TD Garden in Boston, where the defending champions moved into the box seat thanks to wins for Andrey Rublev, Matteo Berrettini and Casper Ruud in the singles on Friday.
John Isner and Denis Shapovalov managed to get Team World on the board in the evening's final doubles match against Alexander Zverev and Berrettini 4-6 7-6 (7-2) 10-1.
Roger Federer and Rod Laver were in the crowd as Team Europe – headlined by newly crowned US Open champion Daniil Medvedev and consisting of six of the world's top 10 – made a strong start courtesy of Norwegian Ruud, who overcame Reilly Opelka 6-3 7-6 (7-4), improving his career record to 3-0 against the towering American, and beating him in straight sets for the first time.
Italian star Berrettini then overcame Team World's Felix Auger-Aliassime 6-7 (3-7) 7-5 10-8 in the competition's longest match at two hours, 52 minutes.
Berrettini escaped with the second set after facing two break points in the penultimate game before prevailing against the Canadian in a thrilling match tie-break.
"One of the best matches bar none that I've ever seen played, absolutely just enthralling," said captain John McEnroe, whose Team World are eyeing their first Laver Cup trophy.
Rublev rallied past Argentina's Diego Schwartzman, who won the opening set and led 6-2 and 8-5 in the match tie-break before losing 4-6 6-3 11-9.
"Today we are a bit more lucky; Matteo won a tough match against Felix in a super tiebreak, now you saw my match," said Russian star Rublev.
"It was so close; Diego was leading all the super tiebreak, but in the end I find a way to win.
"This happens. This is tennis, this is sport. It’s emotions. Someone has to win, someone has to lose."
On day two, Stefanos Tsitsipas and Zverev headline the day session against Team World's Nick Kyrgios and Isner.
In the evening, Medvedev will meet Shapovalov before Rublev and Tsitsipas team up for a doubles battle with Kyrgios and Isner.
World number two Medvedev prevailed 6-4 6-3 in Toronto on Sunday as he became the first Russian to win the ATP tournament since Marat Safin in 2000.
Medvedev now holds four of the nine ATP Masters 1000 titles, having also previously come out on top in Cincinnati, Shanghai and Paris.
He saved all four break points faced against unseeded Opelka, who stunned Stefanos Tsitsipas in the semi-finals, and needed just 85 minutes to complete the job.
Reflecting on his latest tour triumph, Medvedev said: "I could not have dreamt of this at one point.
"With Novak [Djokovic] and Rafael [Nadal] playing, it seemed like an untouchable achievement. Now I have four wins in five finals, which is a good score. I am just happy.
"Playing Canada and Cincinnati, the goal is to win as many matches as possible. I was able to do it two years ago and I will try and do it again."
Opelka was competing in his maiden final at this level and started strongly, racing 40-0 ahead in the fourth game with some powerful hitting.
However, the 23-year-old – the first American to reach the final since Mardy Fish in 2011 – could not break his opponent as Medvedev recovered with some impressive serving to take the game.
Medvedev earned the first break in the following game and comfortably held to take the first set.
The Russian forced Opelka into errors in the second set and reeled off nine points in a row en route to breaking his opponent in the third game.
It was plain sailing from that point on as two-time beaten grand slam finalist Medvedev eased over the line to add another trophy to his collection.
Top seed and world number two Medvedev appeared headed for another defeat to Hurkacz before fighting back to prevail 2-6 7-6 (8-6) 7-6 (7-5) and reach the semi-finals.
The Pole won a five-setter at Wimbledon in the pair's only previous meeting before going on to stun Roger Federer and reach the semis, but could not repeat his feat in Toronto.
Though Medvedev failed to convert the only two break point opportunities he had, his work in the tiebreaks was enough to put him over the top as he served 23 aces to nine for Hurkacz.
The Russian now faces a semi-final matchup against John Isner, who won a clash of veterans with 11th seed Gael Monfils 7-6 (7-5) 6-4.
Earlier Friday, Tsitsipas claimed a 6-1 6-4 victory over Ruud, who entered the clash having won each of his previous 13 matches.
It was Tsitsipas' 45th win of the season, a figure unmatched by anyone else on the ATP tour, and he needed just 74 minutes to complete it.
The 23-year-old won each of the first five games of the match and only made four unforced errors in the opening set.
Although Norway's Ruud improved in the second, he failed to make the most of a rare break opportunity and that seemed to jolt Tsitsipas into life again, the Greek swiftly breaking and then serving out the match.
"It is very nice to see myself perform at this level," Tsitsipas said afterwards. "I was sticking close to the baseline and coming in, taking the ball early. It was my intention from the very beginning, and it worked perfectly.
"Playing against a guy like him, who gets every single ball back, is always very challenging. There is some sort of concentration levels you have to reach to perform to your best. These kinds of matches always teach me things that I can expose for next time."
Up next for Tsitsipas as he targets a place in the final is Reilly Opelka, the big-serving American who defeated Roberto Bautista Agut 6-3 7-6 (7-1), plundering 18 aces along the way.
World number 32 Opelka fought back from a set down in Toronto to knock out favoured third seed Tsitsipas in two hours and 32 minutes.
The 23-year-old American triumphed 6-7 (2-7) 7-6 (7-4) 6-4, booking a spot in his first ATP Masters 1000 final.
Opelka sent down 17 aces but also hit 27 groundstroke winners in the shock victory over 2021 Australian Open semi-finalist Tsitsipas who had beaten in-form Casper Ruud in the quarters.
"I played great," Opelka said in his on-court interview. “These courts suit my game, it is no coincidence that John Isner is in the other semi-final.
"Stefanos has definitely improved his returning. Come 5-5 in the first set, a lot of balls started to come back. He is a thinker and has a high tennis IQ, so it was expected, but that is what separates him from the rest of the pack."
Opelka was aided by an excellent first serve percentage of 72 per cent, winning 62 of 81 points when he made his first serve.
Both first two sets went to tiebreaks, with Tsitsipas failing to generate a break point until the third set. Opelka made the first break of the match in the seventh game of the third set and held serve twice after to seal victory.
World number two Medvedev cruised into the decider with a commanding win over John Isner in less than an hour.
Medvedev, who was runner-up in Toronto in 2019, won 6-2 6-2 over the big-serving American, with the match totaling 54 minutes.
Isner could only manage four trademark aces for the match, while the Russian had 11 and broke the American four times from seven opportunities.
Blocking Murray's way to a first ATP Tour title since October 2019 will be Russian player Aslan Karatsev, whose gritty win over Dan Evans prevented an all-British final.
Evans won a marathon tie-break in the second set of that encounter but could not maintain the level as he lost out 6-3 6-7 (13-15) 6-3 to a player who caused a sensation by reaching the 2021 Australian Open semi-finals.
It was also a case of digging deep for Murray, who picked up a stellar win over American Reilly Opelka, triumphing 6-7 (6-8) 6-4 6-4 against the fourth seed and world number 25. Murray is ranked down at number 135, but this strong week has provided evidence he still belongs at a much higher level.
Three years have passed since Murray came to Australia and indicated he was close to retirement due to hip trouble. He has battled back against the odds to stay active, but his lone ATP singles final appearance since that point came at the 2019 European Open in Antwerp, where he beat Stan Wawrinka to land a surprise title.
Now he is back in another title match, for what will be just his fourth singles final on the main tour since the end of the 2016 season, when he reached world number one status.
Murray rifled 16 aces and no double faults, winning an impressive 88 per cent of points when he landed his first ball in court, and his serve was not broken at any point by Opelka.
He has 46 singles titles and dearly wants to reach 50 before calling it a day, with a glorious chance to land a 47th coming up on Saturday.
Karatsev, the world number 20, is not a player that Murray would underestimate. He was ranked 114th and largely unknown before going on his run to the final four in Melbourne last February, but he has since pushed on and should provide a stiff test for three-time major winner Murray.
"It's already been a great week for me, big progress from anything I've done in the last year or so, to string four matches together like this and against top players in Basilashvili and Opelka," said Murray. "I'll go for 47 tomorrow. It's been a good week, I've played better with each match, so hopefully I'll step it up again."
At the Adelaide International 2 event, Australian wildcard Thanasi Kokkinakis produced a stunning semi-final win over fourth seed Marin Cilic, battling to a 6-2 3-6 7-6 (12-10) victory over the former US Open champion, teeing up a shot at Frenchman Arthur Rinderknech in the title match.
Coming off an epic three-hour duel Wednesday in his first match since the French Open final, Nadal fell to Lloyd Harris 6-4 1-6 6-4 on Thursday at the Citi Open.
After a short-lived maiden appearance at the Washington, D.C. tournament, the Spaniard will look ahead to Toronto and Cincinnati as he continues his preparations for the U.S. Open.
Harris, meanwhile, heads to a quarter-final matchup against veteran Kei Nishikori after recording the biggest win of his career.
Facing Nadal for the first time, the 24-year-old South African slammed 16 aces Thursday and saved four of six break points.
The 20-time grand slam winner, who battled a foot injury to outlast Jack Sock in his first match, did not have enough to answer the world number 50 on Thursday.
In addition to the top-seeded Nadal's defeat, second seed Felix Auger-Aliassime also went down Thursday, falling 6-3 6-4 to American wild card Jenson Brooksby.
With their exits, the tournament is now without its top four seeds.
That leaves fifth seed Jannik Sinner as the top player remaining after he defeated Sebastian Korda 7-6 (7-3) 7-6 (7-3).
Nishikori advanced by downing seventh seed Cameron Norrie 3-6 6-3 6-3, while John Millman knocked out eighth seed Reilly Opelka 6-3 7-6 (7-4).
Among unseeded players, Denis Kudla defeated the red-hot Brandon Nakashima 3-6 7-6 (7-3) 6-4, while Steve Johnston eased past Ricardas Berankis 6-2 6-1 and Mackenzie McDonald beat Illya Ivashka 6-4 6-4.
In addition to Harris-Nishikori, Kudla will face McDonald in the other quarter-final in the top half of the draw, while Sinner meets Johnson and Millman takes on Brooksby in the bottom half.
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.
The 19-year-old Californian Nakashima, ranked 115th in the world, prevailed 5-7 6-3 7-6 (7-4) over world number 22 Raonic in their first meeting.
The big-serving Canadian had 10 double faults to go with his 27 aces, while Nakashima did not commit one double fault and managed 13 aces.
It was the latest in a string of recent wins over established players for Nakashima, who stunned Sam Querrey and John Isner last week at Los Cabos before falling to Cameron Norrie in the final.
Nakashima next faces Australia's Jordan Thompson, who beat Peter Gojowczyk of Germany 7-6 (8-6) 6-4 to reach the quarter-finals.
In the other half of the draw, fifth seed Taylor Fritz rallied to defeat fellow American Steve Johnson 6-7 (5-7) 6-4 6-1 in a rematch of a quarter-final at Los Cabos, also won by Fritz.
Fritz will face countryman Reilly Opelka, who outlasted Bjorn Fratangelo 7-6 (7-3) 7-6 (7-4). The 6-foot-11 Opelka pounded 25 aces to just three double faults, winning 84 per cent of his service points.
Norrie eventually overcame the American fifth-seed after a final set tie-break, winning 6-2 1-6 7-6 (7-4).
The Brit's tenacity was key, saving seven of 10 break points, and he will now face another American, Tommy Paul, in the final four in Florida after he beat qualifier Stefan Kozlov 6-3 6-1.
The other semi-final will be contested between Reilly Opelka and John Millman after they bested Adrian Mannarino and Grigor Dimitrov respectively.
Opelka was taken to a third set by his French opponent before winning 7-6 (7-2) 3-6 6-1, hitting 19 aces on his way to victory.
Millan proved too good for third seed Dimitrov winning 6-4 6-4 in an hour and 34 minutes where the Australian's return was a highlight.
At the Rio Open, rain washed out many of the scheduled matches on Friday, with Diego Schwartzman against Pablo Andujar and Miomir Kecmanovic against Francisco Cerundolo both cancelled.
Matteo Berrettini and Thiago Monteiro were finally able to finish their round of 16 match at 11.35pm local time, with the Italian securing victory 6-4 6-7 (6-8) 6-3.
He will play seventh seed Carlos Alcaraz who overcame Federico Delbonis 6-4 7-6 (7-1) after their match was pushed back, starting not long prior to midnight local time.
