A 6-2 7-5 loss to Schwartzman in Rome ended Nadal's 100 per cent record in their rivalry, after nine previous wins for the Spaniard.
In their fifth clash on clay, and first on the surface since Nadal won in four sets in the 2018 Roland Garros quarter-finals, Schwartzman wobbled with victory in sight.
At 5-4 ahead in the second set he was broken to love by 12-time French Open winner Nadal.
But the eighth seed magnificently broke back immediately and then held his nerve to complete a memorable success, finishing with a volley at the net out of the reach of the stranded Nadal.
The result ends the prospect of a final between Nadal and top seed Djokovic on Monday, with Schwartzman moving on to tackle Canadian Denis Shapovalov in the last four of the tournament.
"Today I played my best tennis. [It was] Very similar to Roland Garros against Rafa three years ago and I'm very happy," Schwartzman said in his post-match interview on court.
"I was not thinking to beat him really because I was not playing good lately. But today I did my best and I'm very happy."
There were clear mitigating circumstances behind Nadal's unusually early exit, given this is his first tournament since February.
The 34-year-old elected to miss the resumption of tennis in the United States last month, skipping the US Open over concerns about long-haul international travel in the coronavirus period.
Shapovalov was a 6-2 3-6 6-2 winner against Bulgarian Grigor Dimitrov earlier on Saturday.
Spanish Sixth seed Ramos Vinolas won 4-6 6-3 6-4 in two hours and 40 minutes to claim his fourth career title.
The 34-year-old, who is ranked 44th in the world, trailed 4-1 in the third set, down two breaks but rallied back to win the next five games to clinch victory.
Tabilo had knocked out top seed Diego Schwartzman in the semi-finals and looked on course for victory after winning the first set when he sent down five aces.
The Chilean got a break ahead in both the second and third sets but could not hold his composure under pressure.
Ramos Vinolas was excellent on his return in the third set converting three of four break points, with the tiring Tabilo failing to have any aces in the deciding set.
The Spaniard, whose last title was in Estoril in 2021, improves to 4-7 in Finals at the ATP Level.
The 20-year-old American, who took a set off Novak Djokovic and rattled the world number one at the US Open, is shaping up as potentially his country's biggest hope for the future in the men's game.
Californian Brooksby crushed Spain's world number 44 Alejandro Davidovich Fokina 7-5 6-0, and second seed Schwartzman awaits after the Argentinian took down another 20-year-old American, Brandon Nakashima, scoring a 6-4 6-2 quarter-final win.
Schwartzman is the man who ended Andy Murray's hopes at the tournament in Antwerp.
Brooksby, who had to win two qualifying matches to reach the main draw, said: "Tomorrow will be a great match. I'm really looking forward to it. I'll get some rest tonight and get ready to battle again tomorrow."
The other semi-final will see Italian top seed Jannik Sinner take on South African seventh seed Lloyd Harris following their respective straight-sets wins over Arthur Rinderknech and Marton Fucsovics.
There will be an all-Russian semi-final at the Kremlin Cup in Moscow, after Aslan Karatsev and Karen Khachanov won through to the final four.
Second seed Karatsev sank the hopes of Frenchman Gilles Simon, breaking serve five times on the way to a 6-4 6-3 win, while third-seeded Khachanov edged out Australian John Millman. A 7-5 7-6 (7-4) grind featured 19 aces by Khachanov, the 2018 Kremlin Cup champion, who saved four set points in the second set.
Marin Cilic thrashed Pedro Martinez 6-1 6-2 to set up a tussle with Ricardas Berankis, the Lithuanian ending Adrian Mannarino's run with a 6-2 7-6 (7-1) success. Frenchman Mannarino had stunned Russian top seed Andrey Rublev in the previous round.
Tommy Paul took down Rublev, beating the fourth seed for the first time in four meetings, while the ninth-seeded Shapovalov fell to Aslan Karatsev.
The news was not all bad for the higher seeds, though, as US Open champion Medvedev picked up his 50th win of the year.
PAUL DOWNS RUBLEV
Playing in the main draw at Indian Wells for the first time, the 24-year-old American Paul outlasted Rublev 6-4 3-6 7-5 for his second win in eight career matches against top-10 players.
Paul was on the offensive throughout the match, firing 41 winners while making 37 unforced errors, while Rublev had 23 of each.
The Russian will lament missed opportunities, as he converted just four of 14 break point chances before watching Paul break him twice in the final set to prevail.
Paul moves on to face 21st seed Cameron Norrie, who beat Roberto Bautista Agut 6-4 5-7 6-3.
MEDVEDEV NOTCHES 50TH WIN
Medvedev had to work a bit to get past 27th seed Filip Krajinovic 6-2 7-6 (7-1), improving to 38-5 on hard courts in 2021. Only Stefanos Tsitsipas (52) has more victories overall this year.
The Russian had 25 winners and 18 unforced errors while winning 70 per cent of points on his first serve.
He next faces 23rd seed Grigor Dimitrov, who downed 16th seed Reilly Opelka 6-3 6-4.
KARATSEV UPSETS SHAPOVALOV
Playing at Indian Wells for the first time, 19th seed Karatsev upset Shapovalov 7-5 6-2, saving the only break point he faced in the match.
Casper Ruud, seeded sixth, rallied past Lloyd Harris 6-7 (4-7) 6-4 6-4 as he seeks his sixth tournament title this year.
He will face 11th seed Diego Schwartzmann, who beat 18th seed Daniel Evans 5-7 6-4 6-0 to reach the fourth round at Indian Wells for the first time.
Eighth seed Hubert Hurkacz had little trouble with Frances Tiafoe, rolling past the American in straight sets.
Jannik Sinner, the 10th seed, advanced via walkover when John Isner withdrew from the tournament to fly home and be with his wife Madison with their third child expected to arrive ahead of schedule on Tuesday.
Rublev – the world number five – won 6-2 6-1 over local 20-year-old Nakashima at the ATP 250 tournament on Wednesday.
Nakashima claimed only two of 18 second serve points for the match, with Rublev breaking him six times and triumphing in one hour, two minutes midweek.
The result improves 2021 Australian Open quarter-finalist Rublev's record to 45-15 this calendar year.
Rublev will take on sixth seed Diego Schwartzman, who rallied to defeat Lloyd Harris 4-6 6-3 6-2 in San Diego.
Fifth seed Hubert Hurkacz moved into the next round with a 7-6 (7-2) 6-1 victory over Australian qualifier Alex Bolt.
Hurkacz will face Russian and 2021 Australian Open semi-finalist Aslan Karatsev in the round of 16.
Daniel Evans – the eighth seed – overcame former Wimbledon and US Open runner-up Kevin Anderson 7-6 (13-11) 7-5 after more than two hours on court.
Evans will meet countryman Cam Norrie next.
Top seed Rublev won 6-1 7-5 in one hour and 52 minutes over the Argentine, who kept on coming throughout the contest.
The Russian world number five's victory books his spot in the last four where he will face Briton Cameron Norrie, who upset fourth seed Denis Shapovalov 6-3 6-1.
Rublev is featuring in his eighth semi-final of the calendar year and chasing his first title since winning in Rotterdam in February.
He had been a break up in the second set after dominating the first, but Schwartzman broke back.
The second set appeared destined for a tie-break with Schwartzman up 40-0 on serve at 5-6, before Rublev won the next five points to claim victory.
"The second set was very tough and enjoyable for the spectators to watch," Rublev said. "Every game was really tough with amazing points and the set could have gone either way."
Second seed Casper Ruud defeated Lorenzo Sonego 6-1 6-4 to book his semi-final spot where he will meet Grigor Dimitrov who beat Aslan Karatsev in three sets.
Ruud's win improved his 2021 record to 45-12, with the 22-year-old Norwegian rising to a ranking of 10.
Top seed Rublev won 6-1 7-5 in one hour and 52 minutes over the Argentine, who kept on coming throughout the contest.
The Russian world number five's victory books his spot in the last four where he will face Briton Cameron Norrie, who upset fourth seed Denis Shapovalov 6-3 6-1.
Rublev is featuring in his eighth semi-final of the calendar year and chasing his first title since winning in Rotterdam in February.
He had been a break up in the second set after dominating the first, but Schwartzman broke back.
The second set appeared destined for a tie-break with Schwartzman up 40-0 on serve at 5-6, before Rublev won the next five points to claim victory.
"The second set was very tough and enjoyable for the spectators to watch," Rublev said. "Every game was really tough with amazing points and the set could have gone either way."
Second seed Casper Ruud defeated Lorenzo Sonego 6-1 6-4 to book his semi-final spot where he will meet Grigor Dimitrov who beat Aslan Karatsev in three sets.
Ruud's win improved his 2021 record to 45-12, with the 22-year-old Norwegian rising to a ranking of 10.
Mannarino ultimately came out on top 5-7 7-6 (7-4) 6-3 but he had to do it the hard way, coming back from match point down to set up a meeting with Ricardas Berankis, who lost only tree games in a 6-2 6-1 win over Federico Coria.
Rublev was never cruising, however, as Mannarino only just fell short in the first set and then took the second to a tiebreak, which he eventually won to turn the tide.
The 33-year-old, who lost to Rublev in the final two years ago, took things up a notch in the decider and did not face a single break point as he got the job done despite the home support.
"The crowd was cheering for Andrey but that is normal," he said after reaching the quarter-finals. "I was happy to play with such a nice atmosphere.
"We have been playing for a long time without fans, so it is nice to enjoy a stadium with crowds now."
Second-seed Aslan Karatsev is now the favourite in Moscow, and the Russian had few issues in a 6-4 6-3 defeat of Egor Gerasimov.
Karatsev will face Gilles Simon next following his 6-3 6-2 win over Mackenzie McDonald, while Pedro Martinez won 6-3 6-4 over Filip Krajinovic to book his passage.
At the European Open in Antwerp, Andy Murray's hopes of winning a first ATP Tour title in two years were ended by number two seed Diego Schwartzman.
The Argentinian trailed 4-1 in the first set but fought back to win 6-4 7-6 (8-6) in his first ever match against the Scot, whose last tour triumph was in Antwerp.
In his on-court interview, Schwartzman said: "It was a pleasure to play against Andy. We had not played before and he is coming back and every week he is playing better and moving better.
"I have a lot of respect because when I grew up playing tennis, I was watching Roger [Federer], Rafa [Nadal], Andy and Novak [Djokovic] and right now playing against him is a pleasure for me."
Seventh seed Lloyd Harris is also into the quarter-finals after a straightforward 6-2 6-3 victory over Jan-Lennard Struff in just 72 minutes, Marton Fucsovics came through 6-7 (5-7) 6-3 6-1 against Roberto Bautista Agut and Brandon Nakashima edged past Henri Laaksonen 7-6 (7-5) 6-7 (5-7) 6-3 to earn the right to face Schwartzman.
Ruud, a French Open finalist and defending champion in Bastad , lacked his usual composure as world number 39 Cerundolo broke him three times to win 6-4 3-6 7-5 on Wednesday.
That marked a first top-10 career victory for Cerundolo after defeating world number five Ruud, guiding him to his first quarter-final appearance at the tournament.
"I'm feeling amazing, I'm really happy," said Cerundolo, whose previous best result was beating world number 24 Gael Monfils. "It's amazing getting my first Top 10 win. It's been the best year so far in my career.
"He's a French Open finalist and was the defending champion here, so it was a big challenge for me and I'm happy to go through."
Aslan Karatsev awaits in the quarter-finals Cerundolo after downing Frenchman Hugo Gaston 6-2 6-4.
Fifth seed Pablo Carreno Busta survived a first-set scare to defeat 2016 champion Albert Ramos-Vinolas 4-6 7-6 (7-5) 7-5.
The victory was Carreno Busta's 250th tour-level triumph and he will next face third favourite Diego Schwartzman, who overcame Elias Ymer in straight sets.
Third seed Alexander Bublik was made to work for a 6-3 3-6 6-2 second-round victory over Jack Sock in Newport and Andy Murray edged past Wimbledon doubles champion Max Purcell.
Murray needed almost two-and-a-half hours to get the better of Purcell, eventually triumphing 4-6 6-2 6-1 to tee up a last-eight meeting with Bublik.
Fourth favourite Maxime Cressy had little trouble in beating fellow American Mitchell Krueger 6-3 6-4 and will next face Steve Johnson, who progressed past seventh seed Jiri Vesely with a walkover.
Benjamin Bonzi, ranked as fifth seed in the United States, eased past Christopher Eubanks in straight sets, while James Duckworth triumphed 7-5 3-6 6-2 over Quentin Halys.
John Isner joined the list of favourites who made the third round in routine fashion, beating Peter Gojowczyk in straight sets 6-3 7-6 (8-6), before top seed Felix Auger-Aliassime faced some adversity against Jason Kubler following the Australian's strong run into the fourth round of Wimbledon.
Auger-Aliassime has a slight advantage, leading 6-4 3-6 6-5 before play was suspended due to poor light. When play resumes, Kubler will serve with a chance to force a third-set tiebreak.
The 2022 US Open and French Open runner-up had struggled past Guido Andreozzi in the first round and followed up that up with a 7-5 2-6 7-6 (7-5) loss to Daniel.
The Japanese qualifier, ranked 125th in the world, won in just under three hours, winning the final three points of the deciding tie-break after Ruud led 5-4.
Ruud had more winners (38-32) but committed 30 unforced errors compared to Daniel's 12.
Taylor Fritz cruised into the last eight with a 6-4 6-4 win over Canada's Denis Shapovalov, setting up a quarter-final with sixth seed Francis Tiafoe, who eased past Feliciano Lopez 6-2 7-6 (8-6).
Fourth seed Holger Rune was too strong for Nuno Borges 6-0 6-2 inside an hour, while eighth seed Alex De Minaur crushed Jacopo Berrettini in just over an hour 6-1 6-0.
Top seed Lorenzo Musetti was a surprise second-round loser at the Chile Open with Jaume Munar triumphing 6-4 6-4 in one hour and 31 minutes.
Fourth seed Diego Schwartzman also bowed out, going down 6-4 4-6 7-6 (7-2) to local Nicolas Jarry.
Jarry will face Yannick Hanfmann in the quarter-finals, while Munar will take on Thiago Monteiro.
The French Open runner-up struggled to get going as he fell to a 7-6 (7-4) 7-6 (7-2) defeat to the world number 180, who was backed by a boisterous home crowd throughout.
Ruud struggled from the off as Peniston forced four break points in the Norwegian's first service game, and his miserable outing was rounded off when his opponent raced into a 5-1 lead before serving out a second-set tie-break.
After claiming the scalp of the world number five, Peniston told the BBC: "I can't really believe it. It feels like a dream. It doesn't feel real.
"I think I've been playing well. Casper is an unreal player and he did so well at the French Open, so I knew it was a tough ask. Four or five years ago I was sitting in the crowd just watching so to be here now is just unreal."
Ruud was not the only big name to fall at the first hurdle, with fifth seed Diego Schwartzman going down 6-1 6-4 against big-serving Sam Querrey to become the fourth of the top five seeds to fail to reach the round of 16.
Second seed and defending champion Matteo Berrettini is the exception after faring much better against another home favourite, cruising past Dan Evans 6-3 6-3, while Stan Wawrinka downed Francis Tiafoe 7-6 (7-2) 6-7 (6-8) 7-6 (7-5), and Denis Shapovalov's clash with Tommy Paul was suspended by darkness at one set apiece.
Elsewhere, world number six Stefanos Tsitsipas progressed through his opening match at the Halle Open, beating Benjamin Bonzi 7-6 (7-1) 1-6 6-3 to set up an enticing last-16 clash with Nick Kyrgios, who bested Daniel Altmaier 6-3 7-5.
Fourth seed Felix Auger-Aliassime also progressed after being taken to three sets, beating Marcos Giron 6-3 5-7 6-3.
Meanwhile, defending champion Ugo Humbert will face a tough round-of-16 match against fifth seed Hubert Hurkacz after the Pole overcame Maxime Cressy 6-4 4-6 6-4.
Schwartzman claimed just the third victory of his career over a top-five opponent, winning 6-7 (5-7) 6-3 6-3 in Sydney.
The world number 13 fought back from a break down in the second set before taking his career head-to-head with Tsitsipas to 2-1 after battling through two hours and 42 minutes on Ken Rosewall Arena.
"I was just trying to think that it was his first match for two months after his elbow [injury], so I was thinking just to try and be in the match," Schwartzman said in his on-court interview.
"I had the chance and I think I was ready. I am very happy because playing against Stefanos and being a set and a break down is not easy, but I found a way."
Argentina, who earlier saw Federico Delbonis defeat Michail Pervolarakis in straight sets, will now face Poland on Wednesday to decide who progresses to the semi-finals.
Poland were comfortable 3-0 winners in their match-up with Georgia, Kamil Majchrzak beating Aleksandre Bakshi for the loss of just two games before Hubert Hurkacz defeated Aleksandre Metreveli 6-7 (5-7) 6-3 6-1.
Pablo Carreno Busta beat Viktor Durasovic 6-3 6-3 to put Spain ahead against Norway, and their win was assured when Roberto Bautista Agut claimed an impressive 6-4 7-6 (7-4) victory over Casper Ruud. Alejandro Davidovich Fokina and Pedro Martinez followed up with a straight-sets doubles win.
"Casper is playing unbelievable tennis, [he did] an unbelievable performance last year, and today I played very good," Bautista Agut said. "I returned very well, I made very few unforced errors and I played aggressively. I try to play matches like this and that is why I am practising hard and I am trying to show this level."
Spain are top of Group A ahead of Serbia, whose match with Chile will go down to a doubles decider.
The Argentinian was staring down the barrel of defeat when he lost the opening set and trailed 5-2 in the second, with Davidovich Fokina unable to convert a match point.
After his opponent failed to capitalise, Schwartzman recovered to win 2-6 7-6 (7-3) 6-1 to set up a semi-final with either Felix Auger-Aliassime or Yoshihito Nishioka.
Schwartzman is aiming to secure one of the final two spots for the ATP Finals and occupies the final qualifying berth.
"Tennis sometimes is crazy," said Schwartzman after the match. "Maybe today I got lucky to be here answering questions.
"But that is why I am here as well with this ranking, because I am always trying to find a way to win the matches. Today was not the exception to the rule."
Home favourite and top seed Alexander Zverev came through in three sets, beating Adrian Mannarino 6-4 6-7 (5-7) 6-4. He meets Jannik Sinner, who recovered from losing eight straight games to defeat Gilles Simon 6-3 0-6 6-4, in the other last-four match.
At the European Open, Dan Evans saved match point en route to ousting third seed Karen Khachanov 3-6 7-6 (9-7) 6-4 and will go up against Ugo Humbert in the semi-finals after the Frenchman beat Lloyd Harris in straight sets.
Alex de Minaur hammered Marcos Giron 6-3 6-0 in under an hour and faces Grigor Dimitrov next, with the Bulgarian handed a walkover after Milos Raonic withdrew before the match due to an abdominal strain.
Second seed Schwartzman, ranked ninth in the world, needed just 81 minutes to seal a 6-3 6-2 victory, setting up a third-round meeting with Alejandro Davidovich Fokina.
It was a less happy outing for third seed Shapovalov in Germany, the Canadian succumbing to a 6-1 4-6 6-2 loss against Gilles Simon.
The result represented a measure of revenge for Simon after the Frenchman lost to world number 12 Shapovalov in the first round of the French Open.
"I am really happy with the way I played, with the focus I had over all of the match," Simon said in his on-court interview.
"I am really happy to beat him, because it is a very, very good win. I had a tough match with him at Roland Garros. I lost it unfortunately, so I am happy that I am the winner this time."
Jannik Sinner awaits for Simon after he defeated Pierre-Hugues Herbert, while Yoshihito Nishioka also made it through.
At the European Open in Antwerp, top seed and home favourite David Goffin suffered a stunning 6-3 7-5 defeat to American qualifier Marcos Giron.
Giron's surprise victory put him in the last eight of a ATP Tour event for the first time and he saved 10 of 13 break points he faced for a maiden victory over a top-20 opponent.
Milos Raonic was not to be denied a place in the quarter-finals, though, and a 7-5 7-6 (7-4) defeat of Cameron Norrie means he will now meet Grigor Dimitrov.
After losing in his two previous finals in Argentina, Schwartzman finally came good in his home city of Buenos Aires with a 6-1 6-2 victory.
The world number nine was in complete control from the off, breaking six times and conceding on his serve just once as he took just 81 minutes to wrap up a fourth Tour title.
Cerundolo's run to the final had at least ensured that whoever came out on top in the showdown would result in the first Argentine champion of the competition since 2008, when David Nalbandian triumphed in a clash with compatriot Jose Acasuso.
"I'm very, very happy, it's been an amazing week for me," Schwartzman said in the trophy presentation.
"It's the first time that [I have won at] home. Two years ago, I reached the final here and lost. I was very unhappy, but two years later I have my revenge against Francisco who is a great player."
Schwartzman also revealed that Vasek Pospisil was eager to add his name to the star-studded executive committee, which includes Hubert Hurkacz and Ons Jabeur.
Speaking to Stats Perform, Schwartzman said: "Well, it took a long time for me to decide and go in. Vasek was trying hard to have me there. Also, ATP always, when they have this selection of the ATP council and the players council, they always try to have me in there.
"My English has been improving over the last few years, so it was good for them to have this kind of combination of a Latin voice, who is English speaking and a strong voice."
Whether it is the mandatory tour events, the short off-season period or the late nights at grand slams, tennis top stars have long called for improved conditions off the court to allow for better quality on it.
Schwartzman, who achieved a career-high world ranking of eight in 2020, admits to having his own battles with the ATP, which led to an alignment with the PTPA.
"I always have strong thoughts, I’m always fighting with the ATP, with the tour managers, with everyone and trying to get better conditions for the players. So, I think that was why I joined PTPA a few months ago," he added.
Since turning professional in 2010, Schwartzman has seen the highs and lows of the sport across his 14-year stint on the Tour.
The Argentine remains competitive with the elite and will no doubt hope to add to the four ATP titles already to his name.
Off the court, he has high hopes that by having 24-time grand slam champion Djokovic at the helm of the PTPA, change across the ATP and WTA Tours is not far away.
Schwartzman said of Djokovic: "He started pushing hard in 2020, 2019. Without the PTPA at that time, pushing for the players, under COVID-19 conditions, it was very hard for us to play the tournaments, with many different conditions, depending on all the different countries and it was tough for us and he had at that time his voice and he was pushing to help the players.
"Then Vasek joined him, and to have this combination between the number one and the guy who has his own voice, and Vasek helping other ranking players, so in the end they are growing very fast.
"I think also with the women now, many different girls have joined PTPA, strong names, and I think that’s very important. As many names as we have, we also have Novak as a main voice. I think that’s very important.
"It was very difficult for tennis to reach because it’s an individual sport, it's always difficult to think as a collective, a group of players because we come from different situations, different countries and it the end Djokovic helps a lot to make us feel like we have a strong voice."
Schwartzman, the top seed in Buenos Aires, needed three hours, 41 minutes to edge Pablo Cuevas 5-7 7-6 (13-11) 7-5 in an epic battle at the ATP 250 tournament.
The Argentinian, last year's runner-up, saved four match points in the second set before overcoming Cuevas.
Schwartzman managed two breaks of serve in the deciding set, including the decisive one in the 12th game.
Awaiting him in the semi-finals is Pedro Sousa, the lucky loser continuing his run with a 7-6 (7-5) 6-4 victory over Thiago Monteiro.
Casper Ruud will face Juan Ignacio Londero in the other semi-final after their respective wins over Dusan Lajovic and Guido Pella.
At the New York Open, Opelka's title defence came to an end with a 5-7 6-4 6-4 loss to qualifier Jason Jung.
Opelka served 24 aces, but the 2019 champion was broken twice to fall to defeat in one hour, 52 minutes.
Jung will meet Andreas Seppi in a semi-final after the Italian veteran got past Jordan Thompson 6-7 (2-7) 6-4 6-1.
Kyle Edmund advanced thanks to a 3-6 6-2 7-6 (7-5) win against Kwon Soon-woo, while Miomir Kecmanovic beat Ugo Humbert 3-6 6-2 6-4.
The Argentine world number 14 had to overcome countryman Francisco Cerundolo 6-3 2-6 5-7 earlier on Saturday after their quarter-final had been interrupted by rain on Friday evening.
The match was tied at 1-1 in the third set when rain intervened, with Schwartzman triumphing when play resumed to earn a semi-final date with third seed Lorenzo Sonego.
Schwartzman would later beat Sonego 7-5 3-6 6-2 in almost three hours on a busy day for the 2020 French Open semi-finalist.
World number eight Ruud progressed with a routine 6-3 6-3 victory over Argentine sixth seed Federico Delbonis.
At the Dallas Open semi-finals, Reilly Opelka and John Isner broke the record for the longest tiebreaker on the ATP Tour since 1990.
Second seed Opelka triumphed over fellow American Isner but it was not easy, winning 7-6 (9-7) 7-6 (24-22).
Opelka sent down 39-21 aces across the match, earning a spot in the final against fourth seed Jenson Brooksby who beat Marcos Giron 6-4 6-7 (4-7) 7-6 (7-5).
Schwartzman reached a final in his homeland for the second time thanks to a 6-1 1-6 6-2 victory over Laslo Djere in their semi-final.
The Argentine top seed landed two breaks of serve in the third set to win in just under two hours and reach the final at the ATP 250 event played on clay.
Schwartzman is into his eighth ATP Tour final and will be aiming for his fourth title when he faces Garin.
Garin, the third seed, was too good for Slovakian Andrej Martin 2-6 6-2 6-2.
The Chilean moved into his fourth ATP Tour final – each of those has been on clay – and is eyeing a third title.
The number one seed continued his impressive form in the tournament by sweeping aside his opponent 6-2 6-2 in just 76 minutes.
Sinner was too powerful for his Argentine opponent and showed just why he is considered to be one of the rising stars of tennis with some breathtaking winners from all over the court in Antwerp, Belgium.
"I felt great on court. I moved well. I also served better, I think," the 20-year old said. "I felt great, but in tennis every day is different. You have to be careful. I think I played well the whole tournament, to be honest, from the first point to the last point.
"I like to play indoors. I tried to push the ball [through the court], which for me was important against Diego because he is moving very well. He's not missing so many shots. For me it was important trying to adapt the game somehow against him.
"I think I can be very proud about the level I played."
