Yet while the world No.1 crashed out in the second round Flavio Cobolli and Matteo Berrettini have made it to the quarter-finals, and Matteo Arnaldi might join them.
Tenth-seed Cobolli dropped his first set of the tournament but beat unseeded American Zachary Svajda en route to a 6-2 6-3 6-7 (3-7) 7-6 (7-5) win.
Later on Monday Berrettini beat Sinner's conqueror, Juan Manuel Cerundolo of Argentina, 6-3 7-6 (7-2) 7-6 (8-6).
Berrettini has missed the previous four editions because of injuries and arrived in Paris ranked 105 in the world. He is thus the lowest-ranked men's quarter-finalist at Roland Garros since 2007 but his ranking belies the ability of the former Wimbledon finalist who has been as high as sixth.
In the evening session Arnaldi is up against American 19th seed Frances Tiafoe with the winner facing Berrettini.
Also into the quarter-finals is fourth-seed Felix Auger-Aliassime who beat Chilean Alejandro Tabilo 6-3 7-5 6-1 and now plays Cobolli.
Cobolli, far more experienced on clay than an opponent ranked 85th in the world, made sure of a solid start and an early break to take control of the first set. A second break landed him the set.
Svajda, making his French Open main draw debut, had only won one match on clay this season going into the tournament, and it showed with the Italian moving far better and the American struggling with a weak second serve.
The 23-year-old Svajda varied his game in the third set, becoming more aggressive and rushing to the net. He did not manage to break Cobolli but snatched the tie-break to cut his lead.
Cobolli looked to have all but finished the job when he broke twice to race to a 4-0 lead in the fourth set but ultimately needed a tiebreak to progress.
Auger-Aliassime eased through the opening set before Toronto-born Tabilo stepped up his game. The pair then went toe-to-toe until Tabilo dropped his serve in the 11th game, enabling Auger-Aliassime to take a two-set lead. He then ran away with the third.
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