It is a bitterly disappointing way to exit the tournament for Sinner, whose favourite tag was enhanced further with defending champion and great rival Carlos Alcaraz missing with injury.
With 24-time Grand Slam-winner Novak Djokovic also nearing the end of his illustrious career, fitness was expected to be one of the biggest obstacles to Sinner's bid for glory.
Paris has seen unseasonably hot weather, with temperatures topping 34C, and Sinner has struggled previously in extreme heat.
Sinner was also on a 30-match winning streak, having won five Masters 1000 titles in a row over the past three months on hard and clay courts.
He cramped badly in temperatures close to 40C at this year's Australian Open, and admitted he "got lucky" when the heat rule was enforced in his third-round match against Eliot Spizzirri in Melbourne.
After opening his campaign against Clement Tabur in Tuesday's cooler night session, Sinner was first on court against Cerundolo in a rare move by Roland Garros organisers.
The last time a men's number one opened proceedings on Court Philippe Chatrier before the semi-final stage was 10 years ago, when Novak Djokovic beat Tomas Berdych in the quarter-finals.
Although Sinner seemed to benefit initially from the early start, the physical issues that have hampered his display in previous matches in extreme heat resurfaced.

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