Andy Murray also saw his campaign come to an end against top seed Matteo Berrettini at Queen's Club.
Many top players saw their campaigns come to an end in Berlin, Birmingham, Queen's Club and Halle.
Birmingham's No. 3 seed soared past Francesca Jones in the opening round and will face Camila Giorgi next.
After a comeback win from two sets down, the world No. 1 is now just one Grand Slam title behind Roger and Rafa.
The Greek will look to lift his first major title and the world No. 1 will try to snatch his 19th.
The 58th career meeting between the tennis titans was a hard-fought battle on the terre battue.
While the American and British duo lifted the mixed doubles title, four women's singles competitors fought to stay alive.
Bold shotmaking, occassional nerves, match point saves, controversy and overtime: this battle of first-time singles Slam semifinalists had it all.
The 18-time major champion set a final four date with Rafael Nadal.
The German posted a dominating 6-4, 6-1, 6-1 score against Alejandro Davidovich Fokina.
The Argentine saved seven set points in the first set against Jan-Lennard Struff and ultimately posted a 7-6 (9), 6-4, 7-5 score.
The 23-year-old became the first woman representing Slovenia to reach the last eight in singles at a major event.
The world No. 18 fist pumped her way into Roland Garros' last 16 for the first time in her career.
The Spaniard saved a match point and ultimately captured a 2-6, 7-6 (4), 6-4 win to advance into the second week at Roland Garros.
The 22-year-old is the first Swedish man to reach the third-round in Paris since Robin Soderling in 2011.
The French Open doesn't have as many fans as it normally does on site this year. Here's a reminder of what it can sound like.
The Greek had another solid day at the office in Paris.
Meanwhile, the 13-time Roland Garros champion Rafael Nadal kicked off his quest for title No. 14.
The 13-time French Open champion has lost just 27 sets in total—can you name the players who've pulled off the feat?
The Russian wasn't the only player to post a first on the terre battue on Monday.