Tsitsipas triumphed 6-1 6-3 in 79 minutes to get past 19-year-old Musetti, who had beaten third seed Diego Schwartzman and former world number three Grigor Dimitrov on his run to the semis.
The Greek top seed will play second seed Alexander Zverev in Saturday's final after the German got past countryman Dominik Koepfer 6-4 7-6 (7-5) in their semi-final, which was literally rocked by an earthquake.
The broadcast cameras shook mid-point but play continued as a 5.7 magnitude earthquake was registered to the north of Marquelia, which is to the east of Acapulco.
Tsitsipas holds a 5-1 record against Zverev, who is ranked seventh in the world and made last year's US Open final.
"Sascha is someone I've played against in the past and it's never easy. We're both really hungry and we're both very competitive," Tsitsipas said.
The Greek made light work of Musetti, winning five straight games in the opening set after starting at 1-1.
Unforced errors cost Musetti, who had his moments, but Tsitsipas was on song with 17 of 23 winners off his forehand.
Musetti will move into the top 100 of the rankings for the first time on Monday after his breakthrough week.
"We'll definitely see a lot from Lorenzo in the future, he has a wonderful one-handed backhand and creates lots of opportunities. He showed his level this week," Tsitsipas said.
The Greek has yet to win an ATP 500 tournament but is now a step closer to ending that record after overcoming his Australian opponent 6-4 6-4 in a little over 90 minutes.
De Minaur's excellent movement was quelled by Tsitsipas, who hit 19 winners and won 27 of 33 first-serve points (82 per cent).
Speaking after his win, Tsitsipas said: "I took my time, I tried to understand what works for me and what doesn't, and with the right momentum, with the right intention, things kind of paid off.
"I was able to get ahead in the score, which gave me a lot of confidence, and I think my serve was very good today, it gave me a lot of points and applied a lot of pressure to him."
Czech qualifier Jiri Lehecka is Tsitsipas' surprise semi-final opponent as the world number 137 continued a fine run by defeating Lorenzo Musetti 6-3 1-6 7-5.
There was a sense of deja vu in the later sessions as Andrey Rublev defeated Marton Fucsovics 6-4 6-3.
Rublev defeated the same opponent in the final of the 2021 tournament, and is now one win away from returning to the showpiece match.
Felix Auger-Aliassime is backing up a strong performance at the Australian Open, where the world number nine was beaten by Daniil Medvedev in the quarter-finals.
The Canadian came through a tough encounter against Cameron Norrie 7-5 7-6 (7-4) as he aims to go one better than his runners-up appearance in Rotterdam in 2020.
Verdasco, the ninth seed at the ATP 500 tournament, was beaten 6-3 6-3 by fellow Spaniard Pablo Andujar on the clay in Brazil.
The 36-year-old has fallen to three straight losses, the first of which was a third-round defeat at the Australian Open.
Verdasco – the 2018 runner-up – was one of three seeds tested, but Garin survived a test against Andrej Martin.
Garin, who won the title in Cordoba earlier this month, needed more than three hours to edge Martin 4-6 7-5 7-6 (7-5).
Albert Ramos-Vinolas departed, the seventh seed falling to 16-year-old Carlos Alcaraz 7-6 (7-2) 4-6 7-6 (7-2) after three hours, 36 minutes.
Federico Delbonis advanced, while wildcard Thiago Seyboth Wild needed almost four hours to get past Alejandro Davidovich Fokina 5-7 7-6 (7-3) 7-5.
There were also upsets at the Delray Beach Open, where John Millman and Adrian Mannarino were beaten in the first round.
Millman, the fifth seed, went down to Yoshihito Nishioka 3-6 6-4 6-2 and seventh seed Mannarino fell to Kwon Soon-woo 1-6 6-3 6-2.
Frances Tiafoe, the champion in 2018, came through his opener against qualifier Emilio Gomez.
The ATP released a statement on Monday saying an unnamed player is now isolating after testing positive for the virus and a contact-tracing process is underway to notify people who may have come into contact with him.
While they did not confirm Querrey was the player in question, the American no longer features on the draw and his first-round opponent, Denis Shapovalov, is now scheduled to play lucky loser Viktor Troicki.
On court, meanwhile, Stan Wawrinka saved three match points to overcome Dan Evans 3-6 7-6 (7-3) 7-5, wildcard Aslan Karatsev saw off Tennys Sandgren 7-5 3-6 7-5 and Cameron Norrie edged past eighth seed Taylor Fritz 6-4 4-6 6-3.
In Cologne, Oscar Otte beat Jan-Lennard Struff in an all-German clash, while Steve Johnson saw off Filip Krajinovic – the fifth seed – in a deciding set.
At the Forte Village Sardegna Open in Italy, teenager Lorenzo Musetti boosted his burgeoning reputation by beating Pablo Cuevas in straight sets, while Jiri Vesely overcame Kamil Majchrzak.
Former world number one Murray pulled off a remarkable win over Russian Roman Safiullin, winning five games in a row from 4-1 behind in the final set.
But that was just a tease for the excitement that followed, as Wawrinka, who like Murray won three grand slam titles in his prime, felled second seed Ruud in straight sets.
The 37-year-old Swiss delighted his home crowd with a 6-4 6-4 victory over this season's French Open and US Open runner-up, serving nine aces as he defied a world ranking of 194th to produce some of his old magic.
Murray has fallen away from the elite ,too, but at 49th in the world he is not far away from rejoining that pack, although defeat looked to be beckoning against Safiullin.
The 35-year-old Scot fist-pumped with relief at recovering the break of serve that Safiullin snatched early in the decider, and Murray hit a service winner on his second match point to seal a 6-7 (5-7) 6-3 6-4 success.
The victory for two-time Wimbledon winner Murray took him to 26 wins this season, the most he has had in a single campaign since pulling off an astounding 78 victories in 2016, the year he won at the All England Club for a second time, landed a second Olympic gold medal and finished top of the rankings.
Murray said of his win: "As the match went on, I started to dictate a few more points and served better."
Quoted on the ATP website, he added: "I changed the way I was returning a little bit, and when I did that, I was able to create a few more opportunities and frustrate him a little bit."
Pablo Carreno Busta scored a 6-2 6-1 win against Argentinian Sebastian Baez, with Alex Molcan, Dominic Stricker and Botic van de Zandschulp also advancing to the last-16 stage.
At the Vienna Open, Murray's fellow British players Cameron Norrie and Dan Evans both went through to the second round, Norrie beating Argentina's Pedro Cachin 3-6 6-2 7-6 (7-1) and Evans fending off Germany's Oscar Otte 6-4 7-6 (7-3).
Canadian left-hander Denis Shapovalov beat Austrian wildcard Jurij Rodionov, but the home crowd had something to celebrate when former US Open champion Dominic Thiem continued his resurgence by eking out a 2-6 7-6 (7-2) 7-6 (8-6) victory against American Tommy Paul, saving two match points.
Wawrinka, the third seed at the ATP 500 event in Acapulco, needed two hours, 45 minutes to edge Frances Tiafoe 6-3 6-7 (4-7) 7-6 (7-1).
The Swiss three-time grand slam champion squandered four match points before battling through.
Wawrinka was the only seed in action on Monday, as two American qualifiers – Tommy Paul and Marcos Giron – progressed.
Adrian Mannarino overcame wildcard Cameron Norrie 2-6 6-3 6-3, Miomir Kecmanovic edged past Alex de Minaur 3-6 6-4 6-3 and Kyle Edmund hammered Feliciano Lopez 6-4 6-1.
At the Chile Open, sixth seed Hugo Dellien got through the first round, while Roberto Carballes Baena and wildcards Thiago Seyboth Wild and Marcelo Tomas Barrios Vera also won.
The WTA Tour's top-ranked player earned $120,150 for winning the title at the Stuttgart Open last week, plus a Porsche sports car, when she beat Australian Open champion Aryna Sabalenka in the final.
Yet for taking the title at the Barcelona Open in the same week, a cheque of €477,795 ($527,000) went to Carlos Alcaraz.
Those tournaments are considered comparable in terms of status and the quality of their fields, yet the difference between the money on offer was striking.
It offered a reminder of the gap between the elite men and women at regular tournaments, despite grand slam events offering equal rewards.
Swiatek and Alcaraz both compete this week at the Madrid Open, where prize money for men and women is equal, the champion of each event collecting €1,105,265 ($1.2m).
Asked about last week's situation, Swiatek said: "Well, it's kind of obvious what my opinion is, because tennis is one of the sports where we speak about equality. I think it's better than most sports anyway.
"But still, there is a lot we can work on in terms of getting equal prize money on some WTA tournaments compared to ATP on the same level.
"Grand slams are already even, as we know. That's nice, but for sure it would be good if WTA would focus on that, but I don't really want to get into that, because it's a lot of business and sometimes politics.
"I don't think I have a lot of influence. I just can say that it would be nice for our sport if it was equal, especially because we kind of do the same work."
The 21-year-old Polish player defended the women's game as she said: "I also get people who are saying that men's tennis is nicer to watch and guys can do more because they are physically and biologically stronger.
"I think there were a lot of people, for example a couple of years ago, who were saying that WTA is not consistent and that's a shame and it should be better, but right now basically I think we are even more consistent than the guys with our game.
"Watching women's tennis gives the same emotions, and sometimes even more emotions, because we are women and we are a little bit more emotional. But, yeah, I think it would be nice if WTA could make it even."
Italian Sinner beat home hopeful Dennis Novak 6-4 6-2 to set up a tantalising showdown with Casper Ruud.
Should he win that match, Sinner will move ahead of Hubert Hurkacz in the race to qualify for this year's ATP Finals, while victory for Ruud will strengthen the Norwegian's standing.
"It's going to be tricky," said Sinner. "He's in a better position than I am for the race. I think right now it's tough to say and tough to do because in the end you try always not to think about that, but in the end you think about that because you believe."
Zverev was given a sterner test, eventually overcoming Alex de Minaur 6-2 3-6 6-2 in one hour and 42 minutes. The Olympic gold medallist will now face Felix Auger-Aliassime, who fought back from a set down to defeat Cameron Norrie.
Frances Tiafoe came from a set down to upset top seed Stefanos Tsitsipas 3-6 6-3 6-4 and earn a quarter-final meeting with Diego Schwartzman after the Argentine overcame Gael Monfils 7-6 (7-5) 4-6 6-2.
In St Petersburg, home favourite and sixth seed Karen Khachanov lost a gruelling three-set encounter to Marin Cilic.
The Croatian, who won the title in Russia in his last appearance in 2011, was 4-1 down in the deciding set but took all five of the final games to triumph after two and a half hours on court.
"Everybody is playing good. The tournament is great. It's the end of the season, so everybody wants to finish on a great level," said Cilic, who next faces Roberto Bautista Agut. "For me, it was great to play this kind of a match today."
Another Russian, Aslan Karatsev, fell to John Millman 6-3 6-2. Taylor Fritz and Botic van de Zandschulp also progressed in straight sets.
Zverev and Brazil's Marcelo Melo were in a super tie-break against Lloyd Glasspool and Harri Heliovaara when they were angered by a call made by the umpire, who overruled a decision from the line judge.
Glasspool and Heliovaara subsequently profited by delivering an ace on match point, which was followed by Zverev quickly walking off and smashing his racquet against the umpire's chair three times.
The world number three then shouted at the umpire that he had "destroyed the whole f****** match" before striking the chair again.
Zverev was due to be in second-round singles action against Peter Gojowczyk, but the ATP Tour confirmed the Olympic champion had been removed from the draw due to "unsportsmanlike conduct".
Former world number one Andy Murray condemned the 24-year-old's "reckless" outburst after his loss to Jannik Sinner, and Zverev has now apologised unreservedly for his raging response.
"It is difficult to put into words how much I regret my behaviour during and after the doubles match yesterday," Zverev wrote on Instagram on Wednesday.
"I have privately apologised to the chair umpire because my outburst towards him was wrong and unacceptable, and I am only disappointed in myself.
"It just should not have happened and there is no excuse. I would also like to apologise to my fans, the tournament, and the sport that I love.
"As you know, I leave everything on the court. Yesterday, I left too much. I am going to take the coming days to reflect – on my actions and how I can ensure that it will not happen again. I am sorry for letting you down."
Zverev was withdrawn from the Acapulco event after an extraordinary outburst during a doubles match where he became angered at a call made the umpire, who overruled a decision from the line judge.
After losing the next point, which was match point, Zverev smashed his racquet against the umpire's chair three times. Zverev then shouted at the umpire that he had "destroyed the whole f****** match" before striking the chair again.
The ATP subsequently withdrew Zverev from the singles draw of the event due to unsportsmanlike conduct at the time and issued a statement on Monday after a review detailing the sanctions, including a suspended eight-week ban for aggravated behaviour.
"The review determined that Zverev committed Aggravated Behaviour under the Player Major Offense section of ATP Rules," the ATP statement said.
"As a result, Zverev has been issued an additional fine of US$25,000 and a suspension for a period of eight weeks from any ATP-sanctioned event.
"However, the fine and suspension are withheld on the condition that, over a probation period ending 22 February 2023 (one year from the incident), the player does not incur a further Code Violation that results in a fine for unsportsmanlike conduct… and verbal or physical abuse."
The German had been fined $40,000 at the time as well as forfeiting full event prize money of $31,570 and all ATP rankings points from the Mexico Open. He has since apologised for his actions.
Second seed Zverev – the defending champion in Acapulco - wrapped up a dramatic win at 04:55 local time after his own lengthy contest had followed two other epic three-setters earlier on the schedule.
Zverev at one stage looked like he was on the way out but ultimately triumphed 3-6 7-6 (12-10) 6-2 to book a second-round tie against Peter Gojowczyk.
The German had beaten Brooksby in a match that also went to a decider when they clashed at Indian Wells in October and he was pushed to the limit again in a battle lasting 200 minutes.
Having dropped the first set, Zverev had to fend off three break points at 3-3 in the second and saved a match point at 6-5 as part of an epic tie-break that went in his favour.
Zverev was then more comfortable as he broke twice in the decider to seal victory, his American opponent paying the price for converting just one of his seven break-point opportunities in a match that made history for its late finish.
Elsewhere, Stefan Kozlov overcame cramps in the second set to outlast Bulgarian Grigor Dimitrov 7-6 (10-8) 5-7 6-3, with that match lasting three hours and 21 minutes.
John Isner sent down 29 aces and saved a match point as he trailed 5-2 in the third set, ultimately winning 7-5 6-7 (4-7) 7-6 (7-3) over veteran Fernando Verdasco in another epic topping the three-hour mark that helped to push back the start time for Zverev and Brooksby.
Seventh seed Taylor Fritz got past Frenchman Adrian Mannarino 6-3 6-3, while Dusan Lajovic knocked off Sebastian Korda 6-4 4-6 7-5 and eighth seed Pablo Carreno Busta beat Oscar Otte in straight sets.
At the Chile Open in Santiago, eighth seed Facundo Bagnis won 6-3 6-0 over Bernabe Zapata Miralles in the round of 32.
Brazilian Thiago Monteiro got past local Nicolas Jarry 7-6 (11-9) 6-4, while qualifier Juan Ignacio Londero and wildcard Thiago Seyboth Wild also progressed.
Second seed Zverev – the defending champion in Acapulco - wrapped up a dramatic win at 04:55 local time after his own lengthy contest had followed two other epic three-setters earlier on the schedule.
Zverev at one stage looked like he was on the way out but ultimately triumphed 3-6 7-6 (12-10) 6-2 to book a second-round tie against Peter Gojowczyk.
The German had beaten Brooksby in a match that also went to a decider when they clashed at Indian Wells in October and he was pushed to the limit again in a battle lasting 200 minutes.
Having dropped the first set, Zverev had to fend off three break points at 3-3 in the second and saved match points at 6-5 and 10-9 down as part of an epic tie-break that went in his favour.
Zverev was then more comfortable as he broke twice in the decider to seal victory, his American opponent paying the price for converting just one of his seven break-point opportunities in a match that made history for its late finish.
The previous latest ATP finish time was Lleyton Hewitt's 2008 Australian Open clash with Marcos Baghdatis, which ended at 04:34 local time.
Elsewhere, Stefan Kozlov overcame cramps in the second set to outlast Bulgarian Grigor Dimitrov 7-6 (10-8) 5-7 6-3, with that match lasting three hours and 21 minutes.
John Isner sent down 29 aces and saved a match point as he trailed 5-2 in the third set, ultimately winning 7-5 6-7 (4-7) 7-6 (7-3) over veteran Fernando Verdasco in another epic topping the three-hour mark that helped to push back the start time for Zverev and Brooksby.
Seventh seed Taylor Fritz got past Frenchman Adrian Mannarino 6-3 6-3, while Dusan Lajovic knocked off Sebastian Korda 6-4 4-6 7-5 and eighth seed Pablo Carreno Busta beat Oscar Otte in straight sets.
At the Chile Open in Santiago, eighth seed Facundo Bagnis won 6-3 6-0 over Bernabe Zapata Miralles in the round of 32.
Brazilian Thiago Monteiro got past local Nicolas Jarry 7-6 (11-9) 6-4, while qualifier Juan Ignacio Londero and wildcard Thiago Seyboth Wild also progressed.
In a battle of the top two seeds, Zverev reigned supreme 6-4 7-6 (7-3) for his 14th ATP crown in Saturday's Acapulco decider.
Last year's US Open finalist Zverev was runner-up at the ATP 500 tournament in 2019, beaten by Australian Nick Kyrgios in straight sets.
But Zverev went one step further this year, taking down two-time Australian Open semi-finalist Tsitsipas after two hours, 17 minutes.
Zverev, who was rocked during his semi-final win over countryman Dominik Koepfer on Friday – a 5.7 magnitude earthquake registered as broadcast cameras shook, did not drop a set throughout his title-winning run.
Greek star Tsitsipas made an impressive start, racing out to a 3-0 lead after breaking Zverev in the second game.
Zverev, though, hit back as he put the set back on serve in the seventh game before consolidating.
Another break saw Tsitsipas come unstuck – Zverev reeling off six consecutive games to claim the opening set in red-hot fashion.
Zverev and Tsitsipas went toe-to-toe in the second set, the pair exchanging breaks late as a tie-break eventually saw the former complete a dominant display.
German star and second seed Zverev accounted for teenager Carlos Alcaraz, the 2019 runner-up winning the opening-round clash 6-3 6-1 on Monday.
Alcaraz – in his first showdown against a top-10 player – broke for a 2-0 lead and while he continued to go toe-to-toe with Zverev through six games, the 17-year-old was unable to maintain his charge.
Zverev broke for a 4-3 lead and the 2020 US Open finalist did not look back, winning nine of the last 10 games to advance in 84 minutes.
"He started off playing extremely well, he didn't miss a lot of balls. Then I felt more comfortable on court, this is the first round," Zverev said.
"It's not always easy to play a first round, especially against a player like this, who is very young, who is very motivated and who wants to compete. I'm actually quite happy with how the match went."
Next up for Zverev – who reached the Australian Open quarter-finals in February – is Serbia's Laslo Djere.
Djere took down Steve Johnson 6-2 6-3 for a spot in the last 16.
Meanwhile, Korda capped his Acapulco bow with a shock 7-5 6-2 win against former world number three Marin Cilic.
Korda claimed his first ATP 500-level victory having saved 10 of the 11 break points he faced in the opening set against the 2014 US Open champion.
Canadian sensation and seventh seed Felix Auger-Aliassime awaits after the 20-year-old converted his sixth match point to see off Tennys Sandgren 6-3 7-6 (10-8).
Elsewhere, John Isner and Dominik Koepfer also advanced.
