Novak Djokovic defeated Jo-Wilfried Tsonga 6-3, 7-5, 6-4 in straight sets.
Garbine Muguruza breezed past her opponent but insisted the clash had not been plain sailing.
Muguruza, who is currently ranked 15th, feels tennis suffers less from sexism than other sports.
Novak Djokovic called for the doctor during the second set against Adrian Mannarino but put aside his discomfort to progress 4-6, 6-2, 6-1.
Muguruza's defeat leaves just top seed Simona Halep, number seven Karolina Pliskova and 10th seed Madison Keys as the remaining top-ranked contenders after two rounds.
Serena, 36, missed Wimbledon last year while preparing to give birth and has endured a rocky time since resuming her career earlier this year.
Simona Halep reached her third French Open final where she will face US Open winner Sloane Stephens for the title.
Simona Halep's victory over third seed Garbine Muguruza also means she will retain the world number one ranking next week.
The 26-year-old Romanian tackles 2016 Roland Garros winner and reigning Wimbledon champion Garbine Muguruza for a place in Saturday's final.
Sharapova, who missed the 2016 tournament because of a doping ban and last year after she was refused a wild card, was broken six times, committed 27 unforced errors and won just five points on her own serve in the second set.
Former champion Garbine Muguruza reached the French Open last 16 with a comfortable 6-0, 6-2 win over Australia's Sam Stosur
Roger Federer remained at the number one spot with 10,060 points.
Garbine Muguruza is set to take on either Frenchwoman Caroline Garcia, the seventh seed, or Russian qualifier Anna Blinkova for a place in the semi-finals.
World number two Garbine Muguruza suffered a fitness scare ahead of this month's Australian Open when she was forced to retire from the Brisbane International with severe cramping.
Simona Halep will be officially confirmed World No.1 next week when the latest rankings are released.
Garbine Muguruza officially became world number one for the first time on Monday.
Five tennis players have a chance to grab the world No 1 ranking at this week's Cincinnati Open.
Women's singles champion Garbine Muguruza asked 19-time Grand Slam winner Roger Federer to dance at the Wimbledon Champions' Dinner.