The 22-year-old Australian breezed past the 15-times Grand Slam champion in about one hour and 20 minutes.
A round-up of all the tennis action from around the globe.
Novak Djokovic's bid for a record 25th Grand Slam title kicked off on Monday with an easy win over qualifier Radu Albot in the US Open first round.
Serena Williams started her quest to join Chris Evert and Martina Navratilova in joint fourth place on the career Grand Slam list with a 6-3, 6-1 victory over 18-year-old fellow American Taylor Townsend at the US Open on Tuesday.
Murray, who suffered an elbow injury in March and made his return from a five-week layoff on Wednesday after a first-round bye, won the opening set in 48 minutes before losing concentration.
World No 1 Novak Djokovic will face Argentina's Juan Martin del Potro, the player who denied him a medal in London, in the opening round of the Rio Olympics after the draw was made on Thursday.
Former world number one Garbine Muguruza was beaten 7-5, 6-4 by Aryna Sabalenka in the China Open second round on Tuesday while an ailing Jelena Ostapenko lost 6-0, 6-0 to Wang Qiang.
It was a repeat of the 34-year-old's straight sets victory over Andy Murray in the second round of the US Open in August.
Sharapova was broken in the first game but fought back to draw level before going on to take the first set with a hold to love.
Images from Day 4 of the 2021 US Open in New York on Thursday.
World No 1s Andy Murray and Angelique Kerber have been named top seeds for the first major of the season, Australian Open, which will commences on January 16.
"Well, I don't know what his intentions are, how he feels, but he is definitely always one of the top favourites in every tournament that he plays," said Djokovic, who beat Slovenian qualifier Aljaz Bedene 6-3, 6-2, 6-4 to join the Spaniard in the second round on Tuesday.
Novak Djokovic began his bid to hold on to his number one ranking with an easy win over Gilles Muller in the Paris Masters second round while Andy Murray struggled through and Stan Wawrinka faltered on Wednesday.
Novak Djokovic sauntered past Spaniard Feliciano Lopez to reach the quarter-finals of the Shanghai Masters on Thursday but Andy Murray had to claw past big-serving American John Isner after losing a first-set tiebreaker.
It will be the earliest meeting between the two since their first professional match in the second round of the 1998 Australian Open.
World number one Novak Djokovic blasted past qualifier Alexei Popyrin 6-4, 6-2 to reach the second round of the Japan Open Tennis Championships in Tokyo.
Djokovic, playing his first tournament for six months because of an elbow problem, dropped his opening two service games and although he battled back to break Monfils twice he wavered again as scrappy opener went his opponents' way.
Defending champion Sloane Stephens was sent packing from the Miami Open on Sunday after a 6-3, 6-2 loss to Germany's Tatjana Maria in the third round.
Belarusian ninth seed Aryna Sabalenka held off a spirited challenge from American Alison Riske to win 6-3, 3-6, 6-1 and successfully defend her Wuhan Open title on Saturday.
The 2020 international calendar concluded with the three tournaments in the Asia leg which was conducted in Bangkok in successive weeks.
World number one Simona Halep saved three match-points before edging past an inspired Lauren Davis 4-6, 6-4, 15-13 in a thrilling marathon to reach the fourth round of the Australian Open on Saturday.
Images from Day 1 of the US Open in New York, on Monday.
World number one Rafael Nadal won a battle of attrition against fellow left-hander Yoshihito Nishioka of Japan 7-6(4), 6-4 to seal Spain's spot in the final eight of the inaugural ATP Cup in Perth on Wednesday. Meanwhile his long-time rival, world number two Novak Djokovic, had an easier outing in Brisbane, strolling past Chile's Cristian Garin 6-3, 6-3 to stay undefeated in the new year.
Nagal said he would look to play more ATP Tour events this year but for that he would have to first improve his rankings.
Garbine Muguruza's preparations for next week's Australian Open were thrown into disarray when the world number three pulled out of the Sydney International with a thigh injury on Wednesday.
IMAGES from Day 1 of the Wimbledon Championships played on Monday.
With the French Open starting on Sunday, Murray has accrued 1,210 to the 4,915 of Rafael Nadal and looks a pale imitation of the player who won his last 24 matches of 2016 to knock Novak Djokovic off his pedestal and seize power in men's tennis.
Images from the Australian Open matches played on Tuesday.
World number five Alexander Zverev continued his poor recent form as he crashed out of the Italian Open in the second round while Serena Williams had to pull out of the women's draw with a recurring knee injury.
Venus Williams staged a spirited comeback to down third seed Petra Kvitova 4-6, 7-5, 6-4 and reach the third round of the BNP Paribas Open in Indian Wells on Saturday.
The seventh-seeded Bulgarian advanced to his eighth ATP World Tour Masters 1000 quarter-final with a 6-3, 7-5 victory over Del Potro, who struggled with the intense heat in the closing stages of the one hour, 39 minute match.
Images from the matches played on Day 8at the Roland Garros on Sunday
Images from Wednesday's matches at Roland Garros
IMAGES from matches played on Day 7 of the French Open at the Roland Garros in Paris on Saturday
Nadal, who got a first-round bye, defeated Richard Gasquet 6-3, 6-4 to advance.
Bernard Tomic is set to sit out the Australian Open after Tennis Australia (TA) decided not to award him a wildcard to the main draw, the organisers said on Thursday.
The Danish World No 3 ended 2017 with the biggest title of her career in Singapore and returned a day after thrashing Madison Brengle in her season opener to hit 21 winners against eight unforced errors in the 53-minute win over Martic.
Karolina Pliskova lost her cool over a line call and bashed a hole into the umpire's chair with her racket after suffering a 3-6, 6-3, 7-5 defeat by Maria Sakkari in the Italian Open second round on Wednesday.
PHOTOS from day four of the Wimbledon championships at the All England Lawn Tennis and Croquet Club in London on Saturday
Images from Day 2 of the Australian Open in Melbourne on Tuesday
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