World number 15 Monfils would have been expected to breeze through against Carballes Baena, whose lone ATP title came back in February 2018.
But Monfils was trounced in the first set and, despite coming back from a break down to win the second, he could not avoid a shock loss as Carballes Baena reversed a 4-1 deficit in the decisive tie-break on Wednesday.
Carballes Baena's triumph sets up a last-eight clash with eighth seed Federico Delbonis, who beat Thiago Monteiro 7-6 (8-6) 3-6 6-4 at the ATP 250 event in Serbia.
Dusan Lajovic also moved through to the quarters after easing past Jeremy Chardy 6-3 6-4, with Andrej Martin the fifth seed's opponent after upsetting third seed Nikoloz Basilashvili 6-1 4-6 7-6 (7-4).
Elsewhere, top seed Lorenzo Sonego suffered a second-round exit at the Emilia-Romagna Open as Sebastian Korda claimed a surprise win.
Korda entered the tournament with just one clay-court win to his name in 2021 but followed up a first-round success over Andreas Seppi with a 6-1 7-5 defeat of Sonego.
Yoshihito Nishioka is his next opponent after the Japanese saw off Lorenzo Musetti 6-3 6-2.
Jaume Munar and Richard Gasquet also progressed, as did Jan-Lennard Struff, Norbert Gombos, Marco Cecchinato and Tommy Paul.
Seeking his third title at the event, world number nine Monfils triumphed 7-6 (7-4) 6-2 in 82 minutes against the Serbian.
Monfils saved all three break points against Krajinovic in an impressive victory that maintains France's perfect record of ensuring a home player reaches the final of the Montpellier tournament.
The 2010 and 2014 champion will meet Pospisil on Sunday after the Canadian defeated David Goffin in three sets.
Goffin served for the match in the decider but lost three decisive games in a row as Pospisil triumphed 6-3 1-6 7-5 in two hours and 21 minutes.
At the Pune Open, Australia's James Duckworth was beaten 7-6 (7-2) 6-4 by Egor Gerasimov in the semi-finals.
The Belarusian dropped only five points behind his first serve as he reached a maiden ATP Tour final, where he will face Jiri Vesely.
Vesely saved match points for the second round in a row, outlasting second seed Ricardas Berankis 6-7 (8-10) 7-6 (7-3) 7-6 (9-7) in a draining encounter to secure a first final in nearly five years.
Moraing, who is ranked 252 places below Djokovic, beat Egor Gerasimov 4-6 7-6 (9-7) 7-5 in a gruelling encounter on Monday.
Djokovic is seeking his 83rd Tour-level title as he warms up for the French Open, the main draw of which begins on May 30.
Fellow home favourite Dusan Lajovic, the highest seed to compete on day one, will meet Jeremy Chardy next after beating Ricardas Berankis in straight sets.
Eighth seed Federico Delbonis required three sets to see off Lukas Klein, while seventh seed Miomir Kecmanovic – another Serbian in the draw – was beaten 6-3 6-2 by Pablo Cuevas.
Veteran Fernando Verdasco set up a contest with Adrian Mannarino after an impressive 7-5 6-2 win over Lucas Pouille.
At the Emilia-Romagna Open in Parma, all of Monday's play had to be cancelled due to persistent rain.
Fifth seed Richard Gasquet is in action on Tuesday.
The top seed had ended a dismal losing streak with victory over Richard Gasquet in the first round and looked to be on course to advance again when he took the first set against Opelka.
But the 6ft 11in American responded to prevail 2-6 7-5 6-4 after successfully defending four Medvedev break points in the third set.
The world number six, who reached the US Open semi-finals before embarking on this desperate run, is the biggest scalp of Opelka's career.
"It is always a tough match, playing one of the best players in the world in general but especially at home," the victor said. "[It is] a great win for me.
"It was ugly for the first set and a half. I felt like I barely won any points on his serve, but part of that is just because of my opponent. Daniil is an absolute nightmare to play."
Medvedev smashed his racket into the court at the end of another frustrating contest.
Russia's other big names will at least fly the flag, as Andrey Rublev and Karen Khachanov progressed.
Rublev's comeback win over Ugo Humbert was a big one for the third seed, who is closing on a place in the ATP Finals. Canada's Denis Shapovalov is also in the running and remains in the hunt for the title this week.
Alexander Zverev eased through at the Cologne Indoors, beating Fernando Verdasco in straight sets, but Marin Cilic exited at the hands of Alejandro Davidovich Fokina.
Cilic led by a set and a break, then had two opportunities to break back in front at 5-5 in the second, before losing 3-6 7-6 (7-3) 6-2.
At the Sardegna Open, Casper Ruud was the victim of the day's biggest upset.
The third seed's prior five defeats since the ATP Tour returned in August had come against top-20 players, but he went down 6-2 6-1 to 101st-ranked Yannick Hanfmann.
Top seed Medvedev looked to have put his shock loss to Vasek Pospisil in Rotterdam behind him when he beat teenager Jannik Sinner in three sets to reach the last eight in the south of France.
However, he lasted just 67 minutes on court as Simon won their quarter-final in a 6-4 6-0 rout, racking up his 29th victory in Marseille, the most he has claimed at any ATP Tour event.
Simon's win sets up a semi-final with Rotterdam finalist Felix Auger-Aliassime, the 19-year-old defeating Egor Gerasimov 7-5 6-2.
Pospisil was unable to earn a second shock victory in as many weeks, losing to world number six Stefanos Tsitsipas 7-5 6-3.
Auger-Aliassime will be the sole Canadian in the last four, with Denis Shapovalov joining Pospisil exiting at the quarter-final stage.
Fourth seed Shapovalov won the second set against Alexander Bublik, but was unable to complete a comeback after losing the first and was eventually defeated 7-5 4-6 6-3.
Top seed Rublev, who won this tournament in 2020, responded to a first-set setback to rally to a 1-6 6-1 7-6 (8-6) win over Tallon Griekspoor on Wednesday.
The world number five was staring at a fourth opening-round defeat in five appearances this year but saved three match points en route to fighting back from 5-2 down in the decider.
Murray and fourth seed Alexander Zverev played out another three-set thriller in the Middle East, with the former world number one triumphing 7-6 (7-5) 2-6 7-5.
That clash lasted three hours and three minutes in another marathon match for Murray after defeating Italian Lorenzo Sonego in a final-set tie-break in the first round.
Medvedev (3) had no such difficulty in a comfortable 6-4 6-3 victory over world number 147 Liam Broady.
Second seed Felix Auger-Aliassime had to regain his composure during his debut in Doha, but ultimately prevailed 4-6 6-1 6-4 against Jason Kubler.
World number eight Auger-Aliassime had lost his only previous meeting with Kubler, and an upset was on the cards after the Canadian was broken in the third game and was unable to recover.
Yet he found his form with a blistering second set, reeling off five straight games to restore parity and keeping his cool in the decider.
That victory teed up a last-eight meeting with seventh seed Alejandro Davidovich Fokina, who downed Kwon Soon-woo 6-3 6-2.
Jiri Lehecka will meet favourite Rublev after beating Emil Ruusuvuori 6-2 7-6 (7-2), while Botic Van De Zandschulp was shocked by world number 170 Alexandre Muller in a straight-sets defeat.
Elsewhere at the Open 13 Provence, fifth seed Maxime Cressy fell to a surprise second-round elimination after a 6-7 (5-7) 6-4 6-3 loss to home favourite Benjamin Bonzi.
There was no such luck for the other Frenchmen in Marseille as Alexander Bublik eased past Gregoire Barrere, while Stan Wawrinka beat Richard Gasquet 4-6 7-5 6-2 to reach the last eight.
Murray – a three-time grand slam champion – defeated Kudla 6-3 6-2 in just over an hour, winning an outstanding 28 of 31 (90 per cent) first-serve points on Tuesday.
The 34-year-old Murray was also on top on return, converting three of four break-point opportunities against Kudla, to complete a comprehensive display.
Murray – currently ranked 116th in the world – will face second seed Ruud next at the ATP 250 tournament.
Elsewhere, Grigor Dimitrov was made to work for his 6-3 1-6 7-5 victory over Hungarian Marton Fucsovics.
Former world number three Dimitrov triumphed in two hours, seven minutes, confirming a spot in the second round, where he will face US Open semi-finalist Felix Auger-Aliassime.
Diego Schwartzman – the sixth seed – progressed with a 6-2 6-3 win over Italian qualifier Federico Gaio.
Young American Sebastian Korda beat Tommy Paul 6-3 5-7 6-1 in more than two hours, while ninth seed Lorenzo Sonego, Cameron Norrie and Lloyd Harris were also victorious.
Two days on from beating Frances Tiafoe in a three-set epic, Murray fell to a 6-4 7-6 (8-6) loss to the second-seeded Argentine in Antwerp.
The three-time grand slam winner, who in January 2019 underwent hip resurfacing surgery, was 4-1 up in the first set but was reeled back in and lost out in a hard-fought contest.
Following the defeat, a frustrated Murray said: "I didn't make as many good decisions as I would have liked in the second set dealing with adversity.
"Mentally I was poor, and my attitude was poor on the court."
Murray is still slated to play in Austria and Stockholm before the season is out, while he could also enter the Paris Masters either via a wildcard entry or going through the qualifiers.
"There'll be a decision on the final Paris wildcard on Monday, but I might even play the qualis there," Murray added.
"Sport is a results business. Play well or poorly doesn't really matter if you lose matches. You need to be winning.
"That's what I want in the last few tournaments. They are really strong tournaments and there are no guarantees the results will come, but I want to win more matches."
Murray chose to play in the event as a wildcard to improve his world ranking and avoid tougher first-round encounters, such as facing Stefanos Tsitsipas at the U.S. Open, and he recovered from going behind in the opening set to ease through his first-round tie.
Humbert, who is ranked 26th in the world, came into the clash 87 places ahead of the two-time Wimbledon winner but failed to make home advantage count as the Scot dispatched of him in just over two hours.
Karen Khachanov, who is the seventh seed in Metz, avoided a similar first-set scare to overcome Alexandre Muller 4-6 6-1 6-3, while Marcos Giron edged past Arthur Rinderknech 3-6 7-6 (7-3) 6-4.
That win sets up a second-round tie with fourth seed Alex de Minaur, with Alejandro Davidovich Fokina sneaking past Gilles Simon 4-6 (4-7) 7-6 (7-2) 6-2 in Tuesday's other match.
Frenchman Benoit Paire crashed out of the Astana Open to world number 97 Egor Gerasimov as he lost 7-5 6-4.
John Millman, the fifth seed, did not endure similar struggles as he recovered from losing the first set to ease past Dmitry Popko 3-6 6-1 6-4.
Meanwhile, Ilya Ivashka coasted past Elias Ymer 6-2 6-4 in just over 90 minutes to secure his second-round berth in the Czech Republic.
The three-time Grand Slam champion, who reached the Surbiton Open semi-finals last week, recovered from a slow start before wrapping up a commanding 6-4 6-3 victory in Stuttgart.
Having missed the French Open to focus his efforts on Wimbledon, Murray lost the opening three games of his clash with the Australian qualifier.
However, the former world number one responded in style, breaking his opponent four times on the way to setting up a last-16 clash with Alexander Bublik.
Bublik, the seventh seed, hit 19 aces and won 36 out of 42 points on his first serve as he overcame Denis Kudla 7-6 (7-3) 7-5.
Nick Kyrgios recorded an impressive 18 aces in his 7-6 (7-3) 6-3 win over Jiri Lehecka, but eighth seed Ugo Humbert was ousted 4-6 7-6 (7-4) 6-4 by compatriot Arthur Rinderknech.
Meanwhile, Botic van de Zandschulp and Tommy Paul were among the seeds to fall at the Rosmalen Grass Court Championships.
Sixth seed Van de Zandschulp went down 4-6 6-2 6-1 against Finland’s Emil Ruusuvuori, and seventh seed Paul was beaten 6-7 (7-4) 7-6 (7-5) 7-6 (7-2) by American compatriot Brandon Nakashima.
But there were no such problems for Karen Khachanov. The world number 23 won 28 out of 30 points on his first serve as he downed Alejandro Tabilo 6-3 6-3.
The Briton lost 6-1 6-3 6-2 to Stan Wawrinka in Paris on Sunday to follow up a second-round departure at the US Open.
In the immediate aftermath of his French Open loss, Murray vowed not to "brush aside" the heavy defeat and insisted he would analyse it to understand the reasons.
Looking ahead to the remainder of a year that has been disrupted by the coronavirus pandemic, the 33-year-old has discussed plans to play two consecutive indoor ATP 250 events in Cologne next.
"I know tournament-wise I'm going to try to play as much as I can between now and the end of the year," he told reporters.
"The plan is to play in Cologne, the two tournaments there.
"Probably the only positive of [going out early] is I will get more time to prepare on the indoor hard courts for that."
Later in the year, Murray hopes to travel to Australia, with the ATP Cup a possibility at the start of next season after he had to withdraw through injury earlier this year.
"We don't know exactly what the rules are going to be for Australia, but it's looking like you'll have to get there very early to prepare for that," he said.
"I'd like to play in the ATP Cup because I was supposed to last year [the 2020 edition], and it looked like a great event – or [I will play] another ATP event on in Australia at the beginning of the year if I'm not in the ATP Cup team.
"My plan is to for sure go to Australia. I just don't know exactly what the exact situation is in terms of what date we would have to go, because by the sounds of it, it's pretty early, like mid-December."
Murray needed less than an hour to record a 6-2 6-0 triumph over the big-serving American, setting up a last-16 meeting with Australia's Max Purcell.
Three-time grand slam champion Murray hobbled out of his last meeting with Querrey at the Wimbledon quarter-finals in 2017, a defeat which marked the start of his injury woes.
But he produced a polished display on the grass to wrap up his eighth career win over the American on Tuesday.
Elsewhere in Rhode Island, eighth seed James Duckworth battled to a 6-2 4-6 6-2 win over Liam Broady, and seventh seed Jiri Vesely raced to a 6-4 6-2 triumph against Spain's Feliciano Lopez.
Meanwhile, Thiem ended a 426-day wait for a Tour-level win by overcoming Finland's Emil Ruusuvuori 3-6 6-1 7-6 (7-5) at the Swedish Open.
The Austrian, who has won 17 career titles, halted a run of 10 consecutive losses on the ATP Tour with his first triumph since he beat Marton Fucsovics at the last-32 stage of the Internazionali d'Italia in May 2021.
The 28-year-old expressed his delight at ending his drought in the aftermath, saying: "It's a long time. My last victory was in Rome in 2021, it feels like a different world somehow.
"Many, many things happened. It was tough, but it was also a very good experience I think, for life in general. I'm so happy that I got this first victory here today."
Thiem will face fourth seed Roberto Bautista Agut in the last 16, while Sebastien Baez will take on Alejandro Davidovich Fokina after the former beat Fabio Fognini in straight sets.
The round of 32 did see two shock exits, however, with seventh seed Holger Rune succumbing to a 6-3 6-3 defeat against Switzerland's Marc-Andrea Huesler, and Nikoloz Basilashvili being forced to retire at one set down against Hugo Gaston.
Also, Francisco Cerundolo beat Pedro Sousa to set up an enticing clash with top seed Casper Ruud.
Making his first competitive appearance since his run to the third round of the Australian Open, Murray rallied after losing the first set to clinch a 4-6 6-1 7-6 (7-4) win in Monday's first-round contest.
The three-time grand slam winner – given a wildcard for the event in Doha – was the master of his own downfall in the opener as a double-fault handed Sonego the decisive break.
Having failed to force a single break point in the first set, Murray dominated the second but was facing an early exit when Sonego forced three match points in the decider, only for the momentum to swing again as the former world number one took it to a tie-break.
Sonego raced into a 3-0 lead, but Murray again came roaring back, squandering one match point when he flicked a backhand into the net but making no mistake second time around.
Murray will face fourth seed Alexander Zverev in the second round, as he bids to reach his first tour-level quarter-final of the season.
Alejandro Davidovich Fokina saw off Constant Lestienne 6-4 6-3, while Murray's fellow Brit Liam Broady saw off qualifier Oleksii Krutykh 6-0 4-6 7-6 (7-2).
Australian duo Jason Kubler and Christopher O'Connell also progressed in Doha.
Stan Wawrinka moved into the last 16 of the Open 13 with a 6-4 6-7 (6-8) 6-4 victory over Zizou Bergs.
Benjamin Bonzi and Alexander Bublik were the other first-round winners, ousting Luca Van Assche and Filip Krajinovic respectively in Marseille.
In his opening ATP Tour match of the year, three-time grand slam winner Murray slipped up 6-3 5-7 6-3 against Bagnis, a player who began the year with a 30-59 win-loss career record.
Left-hander Bagnis rose to the occasion on Rod Laver Arena to earn the scalp of the former world number one.
Murray, down at 134th in the rankings after another injury-hit year, is looking to make headway on that front in 2022 under new coach Jan de Witt, so that he can avoid having to take wildcards into tournaments.
He was allowed into this tournament by that back-door route, and has also been confirmed for an Australian Open wildcard, but the Scot could not find the form that saw him beat Rafael Nadal at an exhibition event in Abu Dhabi in late December.
Bagnis said of his win: "In the beginning it was a pleasure to play against Andy and right now to beat him is amazing. I'm really happy."
He added, according to the tournament website: "Yesterday, I came to see the stadium, to see it all around because the atmosphere is different when you play on any court outside… I enjoyed it a lot. It was so good for me."
Nadal was also back in action on Tuesday, playing his first match on the main tour since August as he teamed up with fellow Spaniard Jaume Munar for a doubles win.
A foot injury meant Nadal's 2021 season ended early, but he warmed up for singles tests that lie ahead by joining Munar for a 6-3 3-6 10-4 win over Argentinians Sebastian Baez and Tomas Martin Etcheverry.
At the Adelaide International 1 tournament, there was a notable first-round win on Tuesday for Australian Thanasi Kokkinakis, who saw off compatriot John Millman 6-4 6-3.
Kokkinakis, a major talent as a youngster, is battling to reassert himself on tour after injury troubles, and beating Millman put his name up in lights for at least one day.
He reflected afterwards on the battle it has taken so far, with last year spent largely living out of a suitcase on the second-tier Challenger Tour.
"It was a gruelling year travelling," said Kokkinakis. "I've played a couple of times [in Adelaide] but just in exhibitions, so to play a real meaningful tournament and beat such a quality opponent, a proven veteran like Johnny, means a lot. I played great, and the support was great, so I'm really happy."
Former world number one Murray went down 6-0 6-1 to last year's runner-up Roberto Bautista Agut in Doha on Wednesday.
It was just the fourth occasion in which the three-time major champion has lost a match while winning only one game or fewer in his career – the last time being a defeat by the same scoreline to Roger Federer at the ATP Finals in 2014.
Murray's fellow Briton Dan Evans also endured a second-round loss, going down 4-6 7-5 6-4 to Alejandro Davidovich Fokina – Bautista Agut's next opponent.
Denis Shapovalov bounced back from his first-round loss to Jiri Lehecka in Rotterdam last week by dropping just eight points on serve as he claimed a 6-4 6-0 victory over Alex Molcan inside 52 minutes.
Next up for the Canadian will be Arthur Rinderknech after the Frenchman came from a set down to defeat seventh seed Alexander Bublik 6-7 (5-7) 6-1 6-4.
Nikoloz Basilashvili faced little trouble in overcoming Elias Ymer 6-4 7-5 and his reward is a quarter-final against Marton Fucsovics, who got the better of Kwon Soon-woo.
Karen Khachanov and Marin Cilic will meet in the last eight after they respectively eliminated Emil Ruusuvuori and Botic van de Zandschulp.
In Marseille, second seed Rublev was made to work hard for a place in the Open 13 quarter-finals by home hope Richard Gasquet.
Gasquet went a break up in the third set and, after surrendering his advantage, stopped Rublev serving out the match to force a tie-break.
However, the world number seven did not waste his next opportunity as he sealed a 4-6 6-4 7-6 (7-3) success.
Aslan Karatsev also booked his place in the last eight, while there were wins for Frenchmen Benjamin Bonzi and Lucas Pouille too.
The former world number one emerged triumphant from a gruelling contest lasting three hours and 45 minutes, the longest three-set match of the 2021 ATP season.
Having warded off two match points in the decisive tie-break, Murray clinched a 7-6 (7-2) 6-7 (7-9) 7-6 (10-8) victory with a drop shot that landed just out of Tiafoe's reach.
"I think that's the first time in my career I've played a 7-6, 6-7, 7-6 [match]. I don't think I've ever played a match like that," said Murray, who next faces second seed Diego Schwartzman. "I think it's the longest three-set match I've played by quite a distance. I'm tired right now, obviously it was an unbelievable battle.
"Nowadays obviously my body is old now. I've played a lot of matches on the tour. I don't mind playing long matches, but that was taking it to another level.
"Brilliant match, amazing atmosphere, thanks to everyone who came and supported. It's just so nice to be back and playing in front of crowds again."
American prospect Jenson Brooksby left his compatriot Reilly Opelka flummoxed as the fifth seed was beaten 6-4 6-4.
Opelka was heard proclaiming Brooksby was the "best player I've played in my whole life" during the second set as he struggled to interpret the 20-year-old's service game. Brooksby will face Botic van de Zandschulp in the next round.
There was another upset when sixth seed Alex de Minaur lost 6-4 6-0 to Brandon Nakashima, who has twice reached ATP-level finals this year and will next face Henri Laaksonen, victorious over Benoit Paire.
Lorenzo Musetti needed two tie-breaks to defeat fellow Italian Gianluca Mager, while Alejandro Davidovich Fokina – quarter-finalist at the French Open this year – eased past Jordan Thompson 6-3 6-3.
At the Kremlin Cup, fifth seed Alexander Bublik suffered a surprise straight-sets defeat to Illya Marchenko, the world number 164 winning by a 6-4 6-3 scoreline.
Adrian Mannarino battled through against wildcard Roman Safiullin, but Laslo Djere lost in three sets to Gilles Simon.
Ricardas Berankis and Egor Gerasimov also progressed, while Guido Pella retired from his match with Pedro Martinez.
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.
The former world number one lost the first set despite leading 4-1 and 5-2, and was pegged back again having broken for a 3-2 lead in the second.
But Murray is renowned for being a fighter on court and so it proved again as the three-time grand slam winner defeated his Georgian opponent 6-7 (4-7) 7-6 (7-3) 6-3 in a match that finished after midnight in Sydney.
It marked further joy for Murray against world number 23 Basilashvili, an opponent he defeated in four sets in the first round of Wimbledon last year.
Murray's fellow Briton Dan Evans continued a perfect start to 2022 as he breezed past Pedro Martinez 6-2 6-3 in 85 minutes without facing a break point.
Top seed Aslan Karatsev defeated Miomir Kecmanovic 7-5 6-4 for his first win of the year, while Reilly Opelka (4), Lorenzo Sonego (5) and David Goffin (8) – who is Murray's last-eight opponent - all coasted through in straight sets.
However, Fabio Fognini (7) was a seed who did fall, as he lost 7-6 (9-7) 7-6 (8-6) to American Brandon Nakashima.
At the Adelaide International 2 tournament, top seed Gael Monfils – who triumphed at last week's Adelaide event – withdrew with neck pain in the deciding set of his second-round tie against Thiago Monteiro.
John Isner (2) also bit the dust against wildcard and home favourite Thanasi Kokkinakis with each set going to a tie-break.
Karen Khachanov (3) and Marin Cilic (4) safely made it through in straight sets against Gianluca Mager and Jaume Munar respectively, but Marton Fucsovics (8) was beaten 6-2 6-2 by Frenchman Corentin Moutet.
Tommy Paul, Arthur Rinderknech and Aleksandar Vukic all progressed.
World number 20 Musetti is still just 20 years old, making him the third-youngest player inside the top-40. The only younger players are 19-year-olds Carlos Alcaraz (world number two) and Holger Rune (world number nine).
The talented Italian has two ATP Tour titles to his name, but none outside of Europe, and he will hope to change that after he advanced to the quarter-finals in Buenos Aires.
Musetti will play Peru's Juan Pablo Varillas next after he prevailed 6-4 6-4 against former world number three Dominic Thiem.
Fifth seed Francisco Cerundolo did his part to set up an all-Argentine quarter-final clash after dominating Jaume Munar 6-2 6-1, but compatriot Diego Schwartzman could not hold up his end of the deal, falling 6-1 6-3 to Spain's Bernabe Zapata Miralles.
Meanwhile, world number seven Taylor Fritz made a winning start to his Delray Beach Open campaign, defeating Ecuador's Emilio Gomez 6-4 6-3.
Fritz will play France's Adrian Mannarino in the quarter-final after the 34-year-old veteran eliminated 24-year-old American J.J. Wolf 7-5 6-2.
Second seed Tommy Paul was too strong for Denis Kudla in a 6-3 6-4 triumph, and he will play Radu Albot for a place in the semi-final after the Romanian emerged the 6-4 6-4 victor against Australia's Aleksandar Vukic.
Musetti, 19, produced arguably the standout result of the day as he dismantled Dennis Novak, wrapping up a 6-1 6-0 win in just 53 minutes.
"It was an incredible match," said Musetti, who has been in impressive form of late and moved to 6-2 for the year.
The Italian reached the last four in Acapulco, where ninth-ranked Diego Schwartzmann fell at his racket.
He added on Tuesday: "From the beginning, I felt so comfortable on the court and hitting the ball. I had really good feelings."
Musetti will face top seed Dan Evans next in Cagliari, where Jan-Lennard Struff had to save five match points before finally seeing off Joao Sousa.
None of the seeds followed Monday losers Guido Pella and Tommy Paul out of the tournament, as John Millman also triumphed. Gilles Simon shook off Stefano Travaglia.
At the Andalucia Open, 17-year-old Alcaraz insisted he still saw room for improvement despite setting up an exciting meeting with veteran compatriot Feliciano Lopez.
Sixth seed Lopez, who turns 40 in September and made his professional bow six years before Alcaraz was born, will be wary of the threat of the self-critical prospect, a 7-6 (7-3) 6-3 winner against Nikola Milojevic.
"I have played a great match and above all I have been with a very high intensity from the beginning to the end," wildcard Alcaraz said, quoted on the ATP website.
"If I had to give myself a grade, it would be a nine [out of 10], because you can always play better."
Lopez defeated Taro Daniel, while number five seed Alejandro Davidovich Fokina came from behind to beat Damir Dzumhur 6-7 (1-7) 6-2 6-2.
