After comfortably winning the first two sets where Sinner offered up only one break point opportunity, the match turned on its head as he closed in on victory.
Where Sinner had previously controlled the rallies with power and accuracy from the back of the court, his strokes were suddenly became 10mph slower.
Sinner was left walking dejectedly around the back of the court, shaking his legs out as he struggled to generate power and chase down Cerundolo’s shots.
After going three break points down when serving for the match at 5-4 up, Sinner doubled over and called for the trainer.
He described feeling nauseous and took an off-court medical time-out but he was a shadow of his usual self when he returned.
Sinner took lengthy off-court breaks at the end of each set, but continued to struggle, walking gingerly, wincing and hunching over his racquet between points.
Cerundolo deserves credit for staying calm, winning the third and fourth set with ease before taking a 4-0 lead in the fifth.
The crowd tried to lift Sinner throughout – as did his coaching team who shouted words of encouragement between games – and he had a brief respite when he held serve to win only his second game of the past 18.
But it was in vain as Cerundolo won the next game on Sinner’s serve to end his career Grand Slam dream for another year.
The defeat was Sinner’s first since February and his first on a clay court this season.
The defeat throws the men’s draw wide open, with Djokovic now having his best chance in recent memory at a record 25th Grand Slam.
Cerundolo’s reward for beating Sinner is a third-round tie against Spanish world number 69 Martin Landaluce or Czech world number 66 Vit Kopriva.
