The reigning US Open champion, given a bye for the first round, lost 6-3 6-4 to his South African opponent, who sits 77 places further down the ATP rankings.
The Austrian has endured a difficult start to 2021. He lost in straight sets to Grigor Dimitrov in the last 16 of the Australian Open and was beaten by Roberto Bautista Agut in the quarter-finals in Doha.
It was a first win over a top-five player for Harris, who was not once taken to deuce on serve during their 72 minutes on court.
"I'm super, super happy with that win. [He is] by far the highest-ranked player I have beat," said Harris. "I look up to Domi a lot so, for me, it is a special feeling. I am really happy. Just the fact that I am playing good tennis, match in, match out now is giving me a lot of confidence.
"I was serving really well. I don't think I faced any break points. I took control of those games and [in] one or two games on his serve, I gave myself a good look. I played some of the important points very well. I am very proud of that."
While Thiem is struggling for form, things are looking far better for Andrey Rublev, who beat Emil Ruusuvuori 6-4 6-4 to stretch his winning streak at ATP 500 events to 21 matches.
The world number eight, who will face Taylor Fritz in the next round, equalled Andy Murray for the second-best winning run at this level of the Tour. Roger Federer (28) holds the record.
Third seed Denis Shapovalov beat Jan-Lennard Struff for the loss of just four games, while Bautista-Agut advanced after opponent Matthew Ebden retired in the first set.
Fifth seed David Goffin was beaten in straight sets by Kei Nishikori, who recorded just his third victory of the year.
Karen Khachanov and Jannik Sinner each advanced after three-setters, while Marton Fucsovics and Aslan Karatsev were also taken the distance before progressing.
Hubert Hurkacz, Lorenzo Sonego, Dusan Lajovic, Aljaz Bedene and Filip Krajinovic also won on Tuesday.
Thiem, last in action in an Australian Open final loss to Novak Djokovic, returned with a 6-2 4-6 6-1 victory over wildcard Felipe Meligeni Alves on Tuesday.
The 2017 champion of the ATP 500 event played on clay in Brazil, top seed Thiem grabbed two breaks of serve in the deciding set.
Having started 2020 with four losses in five matches, Borna Coric found a victory by overcoming Juan Ignacio Londero 7-6 (7-5) 7-5.
Dusan Lajovic joined Thiem and Coric as the three seeds to win, but two fell in the opening round.
Casper Ruud, coming off a title win at the Argentina Open, went down to qualifier Gianluca Mager 7-6 (7-4) 7-5.
Guido Pella, the 2016 runner-up, was edged by Thiago Monteiro 5-7 6-4 7-6 (7-3) after just over three hours.
At the Delray Beach Open, Sock claimed his first non-Laver Cup singles win since late 2018.
The American 2017 champion, a wildcard, battled past last year's winner Radu Albot 3-6 6-3 7-6 (7-2), saving a match point in the final set and breaking down in tears following his victory.
Canadian second seed Milos Raonic brushed past lucky loser Denis Istomin 6-2 6-2 and Reilly Opelka served 20 aces in a 6-7 (5-7) 6-4 7-6 (7-4) victory over Ernests Gulbis.
Ugo Humbert, the French sixth seed, battled through, while third seed Taylor Fritz fell to qualifier Cameron Norrie 6-4 6-7 (4-7) 6-4.
Djokovic, whose decision not to be vaccinated against COVID-19 caused him to be deported from Australia on the eve of the year's first grand slam, eased to a 6-3 6-3 win over Lorenzo Musetti in his first match and made similarly light work of Karen Khachanov on Wednesday.
The world number one has won in Dubai on five occasions, last doing so in 2020, having elected against defending his title last year.
However, the Serbian is looking good to regain the crown in what is his first tournament on the ATP Tour in 2022, after he was unable to feature in Melbourne.
Djokovic needed 98 minutes to see off Khachanov 6-3 7-6 (7-2) and tee up a quarter-final tie against qualifier Jiri Vesely.
"I missed it [playing competitively]. This is my life," Djokovic said, with his previous competitive appearances coming in the Davis Cup Finals in November and December.
"This is what I have known for the past 20 years. Tennis is my love. I enjoy bringing positive energy and memories for people who watch."
It was not all plain sailing for Djokovic, who offered up four break points, but the 34-year-old clawed back three of them.
"I was feeling excited and motivated," added Djokovic, who has progressed to the quarters in Dubai every time he has featured at the tournament.
"But also at the same time I was feeling stressed. Particularly at the moments when I was facing break points. I thought the atmosphere in the stadium was terrific."
Djokovic, who will lose his place at the top of the ATP rankings if Daniil Medvedev triumphs in Acapulco, should have little trouble in sealing a semi-final spot, though Vesely does come into that tie on the back of a surprise 6-2 6-4 win over world number 15 Roberto Bautista Agut, who had triumphed in Doha last week.
Murray falls short of landmark win
Second seed Andrey Rublev came from a set down to defeat Kwon Soon-woo 4-6 6-0 6-3, and will go up against American Mackenzie McDonald for a place in the last four.
There was no such joy for former world number one Andy Murray, however, who fell to Jannik Sinner 7-5 6-2.
"It is a special feeling [to share the court with Murray]," said Sinner, who will next face Hubert Hurkacz, a 6-3 6-2 winner over Alex Molcan.
"He is a legend. Winning three grand slams, many, many tournaments and he has had some unfortunate moments with surgeries. His fighting spirit is incredible.
Murray was chasing a 700th tour-level win of his career but failed to muster a single break opportunity against the Italian, who made it to the quarter-finals in Melbourne last month.
Sinner was on the cusp of another final after his triumph in Antwerp last weekend when he led 5-2 in the second set, but qualifier Tiafoe roared back to win 3-6 7-5 6-2 on Saturday.
Italian Sinner had moved into the last qualifying position for the ATP Finals by beating Casper Ruud to reach the semi-finals in the Austrian capital and appeared destined to extending his winning run.
The 49-ranked Tiafoe had other ideas, winning five games in a row to force a deciding set.
Tiafoe maintained his momentum, breaking twice in the final set to complete an astonishing comeback and leave seventh seed Sinner shellshocked.
Second seed Zverev earlier marched into his fifth tour-level championship match of the season with a 6-3 6-3 defeat of Spanish teenager Carlos Alcaraz.
Zverev, who this week secured a 50th tour-level win of the season and a 300th of his career, needed only 68 minutes to knock Alcaraz out.
The German said: "I finally found my rhythm from the baseline because I was really struggling.
"I didn't feel the ball well and I spent some time on the court after the match yesterday and warmed up for an hour and a half before the match today and I finally got it."
Marin Cilic and Taylor Fritz will do battle in the St Petersburg Open final following contrasting wins over Botic Van de Zandschulp and Jan-Lennard Struff respectively.
Cilic did not face a break point in a 6-3 6-3 victory over Dutchman van de Zandschulp, while fought back to defeat Jan-Lennard Struff 5-7 6-1 6-3.
With his 20th birthday approaching on May 5, world number two Alcaraz will have the chance on Sunday to land his ninth ATP title as a teenager.
Alcaraz crushed the hopes of first-time Barcelona semi-finalist Dan Evans, racing to a 6-2 6-2 victory over a player who was seeking to become the first British finalist at this tournament.
Earlier, Tsitsipas, who had not dropped serve en route to the semi-finals, had to dig deep for a 6-4 5-7 6-3 victory against Lorenzo Musetti, the Italian who beat Novak Djokovic in Monte Carlo last week.
Greek star Tsitsipas bizarrely has a 0-9 record in finals at ATP 500 level, the tier at which this tournament sits, despite having won two of his six title matches in elite ATP 1000 events.
Alcaraz will start as a firm favourite in the final. He holds a 3-0 career head-to-head lead over Tsitsipas from their past meetings, including a three-set win in the Barcelona quarter-finals last year.
That was a stormy encounter, with Alcaraz taking exception to almost being hit by a shot from Tsitsipas at the end of the opening set, so the rematch could be one to savour.
"It's so special to play a final here in Barcelona, a tournament I love playing," Alcaraz said on Prime Video. "I came to watch this tournament when I was very, very young, and I played for this club when I was 12, 11. I love this club, I love this tournament, and it's so special to have the chance to lift the trophy here again.
"Last year [against Tsitsipas] we had a spicy match, but I know he's a really nice guy off the court."
At the BMW Open in Munich, it was much the same story on Saturday.
Defending champion Holger Rune, another 19-year-old with a birthday approaching, in his case on April 29, earned another shot at the title.
Rune set up a Sunday showdown against Botic van de Zandschulp, in what will be a repeat of last year's final.
A resilient Rune lived up to his top seeding by ending Christopher O'Connell's fine run, which included a win against Alexander Zverev at the last-16 stage.
The 6-3 6-2 outcome masked the fact Rune saved eight break points as unseeded world number 82 O'Connell threatened to make it a tighter contest on the scoreboard than it turned out to be.
Van de Zandschulp then scored a fine win in the second semi-final as the Dutch fourth seed got the better of American second seed Taylor Fritz, winning 6-4 7-6 (7-2)
Last year's trophy match ended in disappointment when Van de Zandschulp retired due to chest pains during the first set, with Rune saying it was "probably the worst way to win a final".
Rune has three ATP titles to his name, with 27-year-old Van de Zandschulp yet to lift a singles trophy.
Stefanos Tsitsipas breezed into the third round of the Barcelona Open with a straight-sets win over Pedro Cachin on Wednesday. Tsitsipas took 79 minutes to see off Argentine Pedro Cachin 6-4 6-2 on Pista Rafa Nadal. The second seed from Greece did not face a break point and won all three that he fashioned to set up a meeting with Canadian Denis Shapovalov, who got the better of Jozef Kovalik 6-4, 6-3. Jannik Sinner, the fourth seed from Italy, eased to a 6-2 6-4 win over Diego Schwartzman at the Real Club de Tennis Barcelona-1899. Cameron Norrie and Lorenzo Musetti will do battle in round three after defeating Pavel Kotov and Jason Kubler respectively in straight sets. Karen Khachanov beat Nicolas Jarry 6-4 6-4, while Grigor Dimitrov, Dan Evans, Alex de Minaur, Yoshihito Nishioka and Francisco Cerundolo also celebrated midweek wins. Rain hit the schedule hard at the BMW Open, where Aslan Karatsev was leading Daniel Altmaie 3-0 in the third set when play was suspended in the only singles action of the day.
Tsitsipas was too good for big-serving American John Isner in a 6-3 6-2 victory in Acapulco midweek.
A two-time Australian Open finalist, having also reached the French Open final four last year, Tsitsipas excelled on serve against Isner.
Greek star Tsitsipas only dropped one point on his first serve – not facing a break point throughout the last-16 contest – while firing down eight aces.
Standing in the way of Tsitsipas and a semi-final spot at the ATP 500 tournament is Canadian sensation Felix Auger-Aliassime.
In a battle of the NextGen, seventh seed Auger-Aliassime saved four of five break points in a 6-3 6-4 win over wild card Sebastian Korda.
Zverev will feature in his third Mexican Open quarter-final in four years after the second seed took down Laslo Djere 6-4 6-3.
Runner-up in 2019, Zverev will next face eighth seed Casper Ruud – who topped Tallon Griekspoor 4-6 6-3 7-6 (7-3) in the quarters.
"I think today what showed the most is that I got better with the match," Zverev said. "I started off extremely sloppy, started off with a lot of unforced errors.
"The longer the match went on the better I started playing and this is something that is very important for me. When I get into a rhythm I feel very comfortable on court and that's how I felt today."
Elsewhere, Lorenzo Musetti's giant-slaying run continued following a 2-6 6-3 7-6 (7-1) victory against Frances Tiafoe.
Musetti earned his first ATP 500 quarter-final as the Italian prepares to meet fifth seed Grigor Dimitrov, who eased past Miomir Kecmanovic 6-4 6-2.
There was an upset after fourth seed Raonic crashed out 6-4 6-2 at the hands of Dominik Koepfer, while sixth seed Fabio Fognini lost 6-4 6-3 against Cameron Norrie.
World number six Tsitsipas has largely failed to find his best form since the ATP Tour season got back underway in August, and he was eliminated in the US Open third round.
However, the 22-year-old defending ATP Finals champion was back at his best in a 59-minute victory over world number 34 Evans on Wednesday.
Tsitsipas struck 24 winners and offered up just one break point – which Evans failed to take – and the Greek was thrilled to return to form ahead of the French Open.
"It's very satisfying to be playing that level of tennis, as I've missed playing on clay," said Tsitsipas, who will face Pablo Cuevas in round two.
"It helps for my confidence. I've watched this tournament on TV since I was very young and I'm delighted to have gotten off to a strong start."
Elsewhere, Benoit Paire was forced to retire hurt against Casper Ruud, while Cristian Garin ended Yannick Hanfmann's run to take a spot in the last eight.
Fifth seed Andrey Rublev also booked a quarter-final berth with a 6-1 3-6 6-2 defeat of Tommy Paul and Felix Auger-Aliassime went down 6-4 6-2 to world number 56 Alexander Bublik.
Bublik pulled off an audacious underarm serve at one point, catching Auger-Aliassime unaware as the Canadian slumped to a shock defeat.
In Wednesday's final match, world number 11 Roberto Bautista-Agut needed just over two hours to see off Dominik Koepfer 6-3 3-6 6-3.
It was neck-and-neck for much of the first set, with neither player losing serve, but Dimitrov appeared to have the upper hand when he got to 6-3 in the tiebreak.
Tsitsipas recovered emphatically, however, the top seed reeling off five successive points to win the set and he went on to book his spot in the second round thanks to a 7-6 (8-6) 6-4 victory. He will face Frances Tiafoe next.
"Grigor is a tough competitor and the level of tennis was really high today. We both competed at our highest [level]," Tsitsipas said afterwards.
"That was great tennis that was being played during the entire match and I got really close to my [best] offence and showed incredible attitude [in] the last game, which was the one that was the most crucial of the match."
Alexander Zverev, seeded second, was also made to work in his first-round clash with Filip Krajinovic.
While he blew the Serbian away in the first set, he found himself 5-2 down in the second as Krajinovic looked set to level the match, but Zverev scrapped his way back and then served to love to win 6-2 7-5. Alex de Minaur awaits the German.
Casper Ruud and Felix Auger-Aliassime, seeded fourth and sixth respectively, were two other high-ranking players who also secured progression, boosting their ATP Finals qualification hopes.
Ruud was pushed hard by Lloyd Harris but eventually outfought the South African in his 7-5 7-6 (7-2) win, while Auger-Alisassime made fairly light work of Ricardas Berankis 6-3 6-2.
Indian Wells champion Cameron Norrie, who is also in with a shot of reaching the ATP Finals, beat Marton Fucsovics 7-6 (7-4) 6-1 to set up a meeting with Auger-Aliassime – the British number one is 11th in the FedEx ATP Race to Turin rankings, one above his next opponent.
At the St Petersburg Open, fifth-seed Taylor Fritz was the highest-ranked player in action and he needed a little over an hour to beat Emil Ruusuvuori 6-1 6-4.
Pablo Andujar defeated Federico Delbonis to set up a meeting with second seed Denis Shapovalov, while Ilya Ivashka beat Laslo Djere for the right to tussle with tournament favourite Andrey Rublev next.
The world number four made a fast start to his match against Filip Krajinovic, winning the opening five games, but fell away to lose in three sets after an hour and 59 minutes.
Tsitsipas is due to represent Greece at the behind-closed-doors Games in Japan, where he will be among the medal favourites.
His racket bizarrely fell apart in the second set against Krajinovic, with Tsitsipas left clutching just the handle as the head broke off when he attempted a backhand.
Despite reaching for a replacement racket, Tsitsipas could not get the better of his 44th-ranked Serbian opponent.
Krajinovic said, according to the ATP website: "He started really well, really aggressively. I could not find my game, could not find my serve, he was overpowering me. But at the end of the first set, I started to feel better, I was going for my shots.
"It paid off in the end. I am happy to beat Tsitsipas, he is an amazing player. I always play well here, and I hope I keep playing well here."
Krajinovic advances to take on a fellow Serbian, Laslo Djere, in the semi-finals, after Djere swept to a 6-2 6-2 win over Georgian Nikoloz Basilashvili.
Spanish second seed Pablo Carreno Busta prevented a third Serbian reaching the final four, beating Dusan Lajovic 7-6 (7-4) 6-3, and he will face Federico Delbonis on Saturday.
At the Nordea Open in Bastad, Sweden, top seed Casper Ruud had his path to the semi-finals smoothed by the withdrawal of scheduled opponent Henri Laaksonen due to injury.
That walkover means Norwegian Ruud will next tackle Roberto Carballes Baena, who beat Slovakian Norbert Gombos 6-4 6-2.
Chilean second seed Cristian Garin bowed out, beaten 6-4 4-6 6-2 by Argentinian Federico Coria. Coria's semi-final opponent will be Germany's Yannick Hanfmann, a 6-4 6-3 victor over French qualifier Arthur Rinderknech.
The 22-year-old Greek did not have it all his own way in the 7-6 (7-5) 6-2 win, but after coming out on top in a tricky first set, he maintained his level and saw off Lajovic.
Tsitsipas had been in good form during wins over Dan Evans and Pablo Cuevas in the previous two rounds, not dropping a set in the process, though world number 24 Lajovic looked likely to pose more of a threat.
And the Serbian appeared poised to take the first set when going 5-3 up in the tiebreaker, only for Tsitsipas to rattle off four points in succession and take the lead.
Although there were then three straight breaks of serve to start the second set, it was mostly plain sailing from then on for world number five Tsitsipas, who once again relished the setting, with up to 2,300 fans permitted to attend the tournament despite the ongoing coronavirus crisis.
"It was a perfect day, sunny, good people, good atmosphere and good clay," Tsitsipas said in his on-court interview. "Dusan is a difficult opponent to play on clay, with a lot of spin and variation in his shots. I think I had to do something extra for the victory today. I will keep working hard."
Up next for the 2019 Australian Open semi-finalist is Chile's Cristian Garin, who impressively fought back from a set down to beat Alexander Bublik 3-6 6-4 6-4 to reach a third semi-final – all on clay – this year.
The other last-four clash will see the in-form Casper Ruud – 7-5 3-6 6-1 winner over Ugo Humbert – face Andrey Rublev, who impressed with his aggression in a 6-2 7-5 defeat of Roberto Bautista Agut.
Having lost a five-set epic against Novak Djokovic in the French Open final, Tsitsipas crashed out in the first round of Wimbledon against Frances Tiafoe.
The Greek welcomed a return to the clay courts in Hamburg, though, as he saw off a battling Koepfer 7-6 (7-2) 6-3 in a productive workout lasting one hour and 44 minutes on Wednesday.
Tsitsipas dropped serve in the first game of the match but immediately struck back and was not broken again in the contest.
He forced plenty of break opportunities – 14 in total – and converted three over the course of the match which proved enough for victory at the ATP 500 event.
Four set points came and went for Tsitsipas as Koepfer served it out at 6-5 to force a tie-break in the opener, but it mattered little when the world number four won four consecutive points to clinch the breaker.
Koepfer led 3-2 in the second set but two consecutive breaks from Tsitsipas ended the contest and ensured he booked a tie against Filip Krajinovic in the last eight.
Sixth seed Krajinovic beat a German opponent to disappoint the home fans for a second straight day, though he needed a deciding set before seeing off veteran Philipp Kohlschreiber 7-5 4-6 6-3.
In the Nordea Open, held in Bastad, fourth seed John Millman was a casualty as he went down in three sets to big-serving qualifier Arthur Rinderknech, who had 12 aces.
There was no such drama for second seed Cristian Garín, though, as he saw off Pedro Martinez 6-3 6-3, dropping serve just once.
After top seed Daniil Medvedev departed the competition a day earlier, Tsitsipas and David Goffin - seeded second and fourth respectively - each suffered upsets to blow the bottom half of the draw wide open.
Slovenia's Aljaz Bedene recorded the biggest win of his career as he cut down Tsitsipas in straight sets, his second triumph over a top-10 player clinched by a 7-5 6-4 scoreline.
"I tried to stay focused, and I delivered," Bedene said shortly after a stunning winner down the line saw him successfully serve out for the match.
"I actually served really well when it was important and kept my cool really, because I was feeling that he [Tsitsipas] was pressuring sometimes.
"I had to stay focused and cool and play my shots, and I delivered. I'm happy with that."
The world number 52 saved five break points in the opener before claiming his first opportunity, and he conceded: "I think he [Tsitsipas] was probably the better player for most of the first set.
"He was serving really well, and I didn't play my game - especially on his service points. I stayed tough, which I had to do, otherwise it would go the other way. I guess the break gave me a boost of confidence."
Bedene will play Felix Auger-Aliassime in the quarter-finals, with the winner potentially meeting NextGen champion Sinner - matched with Pablo Carreno Busta - in the last four.
Sinner, still just 18, came up with 27 winners to see off 10th-ranked Goffin 7-6 (9-7) 7-5.
"I feel great, especially now in this moment," the Italian said, according to quotes on the ATP Tour website. "It was not easy playing against him. He is very solid, so you sometimes go for a winner or change the rhythm.
"It feels like a normal victory, but sometimes you play better than others. It's all about improving and testing where you are."
Reigning champion Gael Monfils prolonged his title defence, beating countryman Gilles Simon 6-4 6-1.
Seventh seed Andrey Rublev also advanced, while Vasek Pospisil could not build on his shock defeat of Medvedev, going down 6-4 7-6 (9-7) to Filip Krajinovic.
World number five Tsitsipas, who was a semi-finalist at last month's Australian Open, defeated seventh seed Auger-Aliassime 7-5 4-6 6-3 in Acapulco.
In a tight contest, back-to-back double faults from Canadian sensation Auger-Aliassime in the eighth game of the third set proved costly as Tsitsipas broke after the pair had held serve throughout the last.
"It got really tight," Tsitsipas said in his post-game interview. "I got a bit lucky with the double faults towards the end of the match.
"I was just persistent. Towards the end I had zoned in 100 per cent. Both of us brought an amazing energy out on the court. Felix is someone I've played a lot and I have huge respect for him."
Greek star Tsitsipas will next play emerging Italian teenager Lorenzo Musetti for a spot in the ATP 500 tournament decider.
Qualifier Musetti, who upstaged third seed Diego Schwartzman in the first round, stunned fifth seed Grigor Dimitrov 6-4 7-6 (7-3) in the final match of the day.
The 19-year-old Musetti will now contest his maiden ATP 500-level semi-final as he prepares to enter the top 100 on the men's tour after just his fourth main-draw appearance.
Alexander Zverev – the German second seed – progressed to the semi-finals with a walkover after eighth seed Casper Ruud withdrew due to a wrist injury sustained in practice.
Zverev will play countryman Dominik Koepfer in the final four after he defeated Cameron Norrie 7-5 6-4, maintaining his run of not dropping a set all tournament.
Tsitsipas lost the opening set to Hubert Hurkacz and also slipped 2-0 behind in the second, yet he dropped only two further games as he progressed 6-7 (2-7) 6-3 6-1.
The world number six, who had failed to register a victory in his previous appearances at the tournament, moves on to face Aljaz Bedene, a 6-2 6-4 winner against Benoit Paire.
Andrey Rublev, the seventh seed aiming to win a third title already in 2020, wasted little time in reaching the last 16, dismissing Nikoloz Basilashvili 6-2 6-3 in under an hour.
Next up for Rublev will be Alexander Bublik, who came through a tense three-set battle against French qualifier Gregoire Barrere.
Fognini, meanwhile, lost in straight sets to Karen Khachanov, the Russian converting four of the seven break-point opportunities that came his way against the fifth-seeded Italian.
Felix Auger-Aliassime lost five straight games in the second set against Jan-Lennard Struff but eventually prevailed in a decider, his 6-3 1-6 6-3 victory booking a clash with 2018 runner-up Grigor Dimitrov.
In the final match of the day, Filip Krajinovic defeated home wildcard Tallon Griekspoor 6-4 6-1.
Tsitsipas claimed his first title of the season by retaining his Open 13 Marseille on Sunday and saw off Carreno Busta 7-6 (7-1) 6-1 two days later.
The second seed put the Spaniard under pressure with rasping returns and was broken just the once to set up a meeting with Alexander Bublik.
Paire saved four match points in a 2-6 7-5 7-6 (7-1) win over 2014 US Open champion Cilic and will face compatriot Richard Gasquet in round two.
Cilic knocked the Frenchman out of the Australian Open in the second round last month, but fell at the first hurdle in the United Arab Emirates.
Paire had lost five consecutive matches against the powerful Croatian, including a five-set battle at Melbourne Park, yet he fended off two match points in the second set and as many in third before bossing a decisive tie-break.
World number 37 Dan Evans claimed the scalp of fourth seed Fabio Fognini, winning 3-6 6-4 7-5 on day two of the tournament.
Fifth seed Roberto Bautista Agut was another to suffer a surpise exit as he went down 7-6 (7-2) 7-5 to Jan-Lennard Struff.
Yasutaka Uchiyama, Filip Krajinovic, Pierre-Hugues Herbert and Nikoloz Basilashvili were also first-round winners.
The ATP 500 clay-court competition was given special permission by local authorities to allow up to 2,300 people to attend on each day, with the tournament originally postponed in July due to the coronavirus pandemic.
And Tsitsipas relished having fans in attendance, which, along with playing against someone he idolised as a youngster, created the conditions that caused him to lose focus for a little while.
"I have a lot of respect for him. He is a very difficult opponent to face, particularly on this surface," Tsitsipas, 22, said of his 34-year-old opponent. "He is a good friend and one of my idols growing up. It was a great match and I enjoyed it.
"There was a certain point in the match when I forgot I needed to win, as I was enjoying the game and the atmosphere, the crowd. I was playing with positive vibes and energy."
Tsitsipas will now meet Dusan Lajovic, who swept aside Karen Khachanov in emphatic fashion, winning 6-1 6-2 in just over an hour.
Casper Ruud was similarly impressive as he saw off Fabio Fognini 6-3 6-3, and he will meet Ugo Humbert – the Frenchman having eliminated Jiri Vesely 6-4 6-3.
Top seed Tsitsipas faced a tough test against 20-year-old Czech qualifier Jiri Lehecka, whose dream run had included a shock win over world number 12 Denis Shapovalov.
The world number four was forced to battle back after losing the opening set, eventually beating the main-draw debutant 4-6 6-4 6-2.
Tsitsipas, whose last final appearance saw him blow a two-set lead over Novak Djokovic in the 2021 French Open showpiece, has yet to claim an ATP 500 title during his career, a record which he will now look to set straight against Auger-Aliassime.
Currently ranked ninth in the world, the 21-year-old had to overcome a stern test of his own against defending champion Andrey Rublev, who sits two places higher in the ATP rankings, to reach the ninth final of his singles career.
After losing a thrilling first set in a tie-break, Auger-Aliassime roared back to claim a 6-7 (5-7) 6-4 6-2 win over the Russian, his first victory over Rublev in three career attempts.
Auger-Aliassime is chasing his first career title, after losing in the final of this same event against Gael Monfils in 2020.
The final will be Tsitsipas and Auger-Aliassime's eighth career meeting. The Greek has won the most recent five, including their only previous meeting on a hard indoor surface, in the final of 2020's Open 13 in Marseille.
The second seed was the highest-profile casualty in the Austrian capital on Thursday, as he succumbed to the Croatian once more 4-6 6-4 7-6 (7-4).
Coric rescued six match points before stunning Tsitsipas at the 2020 US Open, while he also triumphed when they collided in the Cincinnati showpiece in August.
The world number 27's chances of completing a hat-trick of victories appeared bleak at a set and break down, but he rallied to force a decider that went the distance, before holding his nerve for another notable win.
Coric's reward is a quarter-final clash with Hubert Hurkacz, who boosted his chances of qualifying for next month's ATP Finals with a 7-5 4-6 6-3 win over Emil Ruusuvuori.
Daniil Medvedev advanced to the last eight after a 6-3 6-3 victory over home favourite Dominic Thiem. Next up for the top seed is Jannik Sinner after the Italian saw off Francisco Cerundolo 7-5 6-3.
Third seed Andrey Rublev's ATP Finals hopes were dented after a 6-3 6-4 defeat by Grigor Dimitrov, who will play Marcos Giron after the American overcame seventh seed Cameron Norrie in straight sets.
Over in Basel, third seed Felix Auger-Aliassime required just 49 minutes to complete a commanding 6-1 6-0 rout of Miomir Kecmanovic for his 10th straight ATP win.
Meanwhile, Stockholm champion Holger Rune continued his momentum by recording a seventh straight victory after seeing off Ugo Humbert 6-4 6-2.
Sixth seed Roberto Bautista Agut enjoyed a straight-sets win over three-time grand slam champion Andy Murray to set up a clash with home favourite Stan Wawrinka, who outlasted Brandon Nakashima in a deciding set.
The second seed will meet Karen Khachanov in the last eight of the ATP 500 event.
His progress was in doubt for parts of his 6-4 4-6 7-5 victory over Hurkacz, the match lasting two hours and seven minutes on Thursday.
But Tsitsipas, the highest seed left in the competition after an early exit for Daniil Medvedev, did not allow Hurkacz a single break point either side of the solitary loss of serve he suffered in the second set.
"I played really well," said Tsitsipas, who has an 8-1 record this year.
"Both of us, we played a high [level] of tennis and didn’t give [away] many break-point opportunities.
"[There were] pretty good serves from both sides and I am really glad that I fought so hard towards the very end. It was exhausting, but it paid off."
It was the fifth straight match between Tsitsipas and Hurkacz that required a final set.
"Hubert is a very tough competitor," added the Greek, who is yet to win an ATP 500 tournament.
"We have played loads in the past. Every single time I go out on the court, I know what to expect.
"He is a fighter and he doesn’t like to give up, so it always makes him a very difficult opponent."
Dusan Lajovic had stunned Melbourne runner-up Medvedev with a straight-sets win on Wednesday.
However, his campaign was ended by Borna Coric, who won comfortably 6-3 6-2 to ensure he will face Kei Nishikori in the quarters.
Veteran qualifier Jeremy Chardy defeated David Goffin, ending the Belgian's hopes of back-to-back ATP titles, and will take on Andrey Rublev in the last eight.
