Sinner arrived in Paris as the favourite for the title having lifted clay-court titles in Monte Carlo, Madrid and Rome, with his main rival and defending champion Carlos Alcaraz ruled out with injury and Novak Djokovic searching for his best form.
But Cerundolo tore up the script in a dramatic clash where he held his nerve even as last year's runner-up Sinner crumbled while on the verge of a big win, sending shockwaves through Roland Garros.
As the temperature climbed over the 30 degrees Celsius mark for the first time in the afternoon, Sinner had already breezed through the first set on the back of a solitary break, and the 24-year-old Italian looked to be in cruise mode.
Cerundolo offered resistance towards the end of the second set, but the 56th-ranked Argentine was left with a mountain to climb after Sinner unleashed a huge forehand winner to double his lead in the match for the loss of only five games.
The four-time Grand Slam champion cooled off with an ice towel in the break and turned up the intensity on his unseeded opponent in the third set to go 5-1 ahead, before he began to struggle and halted play when serving at 5-4.
Sinner returned from an off-court medical timeout five minutes later and was immediately broken for 5-5, and dropped the next two games to hand the set to his Argentine opponent, who sensed the chance to pull off a major upset.
Still not at his best, Sinner surrendered the fourth set tamely and was broken early in the decider, as Cerundolo took full advantage to leave the Grand Slam without its title favourite.
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