Coughing between points on an overcast day, the second-seeded Sharapova was outplayed throughout a 7-6 (3), 6-4 loss to 13th-seeded Lucie Safarova of the Czech Republic in the fourth round Monday.
It is Sharapova's earliest defeat at Roland Garros since 2010, when she was beaten in the third round. Since then, the Russian has won the clay-court Grand Slam tournament in 2012 and 2014, was the runner-up to Serena Williams in 2013, and reached the semifinals in 2011.
In another fourth-round match, Serena Williams looked curiously flat at times against Sloane Stephens but still fought back from a switched-off first set to win 1-6, 7-5, 6-3.
Stephens threw everything at Williams, literally. In the eighth game of the third set, she tossed her racket at a ball that fizzed past her forehand.
But it is Williams, not Stephens, who will be the only U.S. woman in the quarterfinals.
On the men's side, Roger Federer triumphed for the fourth time in four matches against Gael Monfils, winning 6-3, 4-6, 6-4, 6-1.
The 17-time Grand Slam champion next plays his Davis Cup Swiss teammate, Stan Wawrinka.
Andy Murray overcame a partisan crowd and Frenchman Jeremy Chardy's strong resistance to remain unbeaten on clay this season and reach the last eight at the French Open for the fifth time.
The third-seeded Murray was whistled and booed several times in his 6-4, 3-6, 6-3, 6-2 win but stayed cool to set up a quarterfinal against David Ferrer, runner-up at the French in 2013.
Against Sharapova, Safarova dictated much of the action and held her nerve as her far more experienced and accomplished foe tried to mount a comeback in the second set.
The left-handed Safarova wound up with a considerable edge in winners, 34-20, including forehands on the last two points to break Sharapova.
In her first French Open quarterfinal, Safarova will face No. 21 Garbine Muguruza of Spain, who beat No. 28 Flavia Pennetta of Italy 6-3, 6-4.
Both of those fourth-round matches were originally supposed to be played Sunday, but were postponed after a rain delay in the afternoon.