Sharapova has reached three consecutive finals at Roland Garros, and won twice, but the number two seed was well beaten by Safarova, who came through 7-6 (7/3) 6-4 to inflict the biggest shock of the tournament so far.
Meanwhile, top seed Serena Williams survived another scare to go through. Williams was in danger of following her rival out of the competition, but the world number one came from a set down for the third consecutive time in Paris to beat fellow American Sloane Stephens 1-6 7-5 6-3.
Sharapova’s exit was surprising, given how she was outpowered by Safarova, with the Czech hitting 34 winners to the Russian’s 20 and breaking serve three times.
“My opponent was at a much higher level more consistently than I was, and that results in a bad day at the office,” Sharapova said.
“I felt like I had small openings and played a good few points, I just wasn’t able to keep that level up today.
“She was able to do that for a longer period of time. She was the much more aggressive player.
“She took the time away from me, created her angles and I didn’t. That was the difference today.”
Sharapova has been suffering from illness during the early rounds and seemed under the weather again.
“I don’t like to talk about it and I don’t think it really makes a difference,” Sharapova said.
“I’m still a competitor, no matter what. I’m going to do everything in order to go out and give it my best and I think I did the best I could.”
Safarova has never made it past the fourth round at the French Open and she will now play Spain’s Garbine Muguruza for a place in the semi-finals. The world number 13, who is likely now to climb into the top 10, had only won one of five previous meetings with Sharapova, but insists she was particularly motivated for their latest match-up.
“I played with Maria the last two times and they were really long battles,” Safarova said. “I almost beat her in Stuttgart, but I always lost. And yesterday I was like really pumped and really ready and just wanted to take this match.”
In the men’s tournament, Novak Djokovic and Rafael Nadal will go head to head in a clay-court clash of the titans after both players sealed their place in the French Open quarter-final.
Djokovic cruised through 6-1 6-2 6-3 against Frenchman Richard Gasquet while Nadal beat America’s Jack Sock 6-3 6-1 5-7 6-2 to set-up a 44th meeting between the duo.
Nadal is bidding to become the first player in the Open era to secure 10 titles at a single major tournament, while Djokovic is hoping to win at Roland Garros for the first time and complete a career grand slam. The Spaniard has won 70 of his 71 French Open matches, but it is Djokovic who is the form player this year, having registered 26 consecutive wins and beating Nadal on clay in Monte Carlo in April.
“He’s by far the best player in the world,” Nadal said. “It is probably the toughest quarter-final of my career here in Roland Garros,” Nadal said.