Sinner led 2–0 in the first set and 5–1 in the third, but by then the problems had crept in.
In over 30-degree heat, the world number one wilted and looked increasingly tormented.
"I had a tough time, started feeling very dizzy and completely out of energy," Sinner said after the match, according to AP.
He had to take a medical timeout while serving for the match, at 5–4 in the third set, and never found his way back.
"It was hot, but not crazy hot. I think it felt totally okay to play. It wasn't really about the heat or the weather at all. It was just me today, but things like that happen," Sinner said.
Cerundolo turned things around and won 3–6, 2–6, 7–5, 6–1, 6–1.
"It's tough for him, he was about to win the match and I couldn't take more than three games in a set. I don't know what happened, if he cramped or felt the pressure. I hope he recovers," Cerundolo said in an on-court interview after the match.
Jannik Sinner was the big favorite to win in Paris this year, especially since world number two Carlos Alcaraz - who defeated Sinner in last year's final - is missing the tournament due to injury.
Sinner thus had his 30-match winning streak, which began in February, snapped, and his dream of completing a career Grand Slam disappeared in the heat. Sinner has previously won Wimbledon as well as the US Open and the Australian Open.
