The Italian had not lost on hard courts to a player other than Carlos Alcaraz for more than a year but a gruelling contest in high humidity against Dutchman Griekspoor proved too much on Sunday.
It became clear early in the third set that Sinner was struggling with his cramp in his right thigh and, despite a visit from the trainer, he decided to admit defeat when down 6-7 (3-7) 7-5 3-2.
The Italian, who had been a huge favourite to retain the title in the absence of world No.1 Carlos Alcaraz, was barely able to walk as he hobbled to shake hands with Griekspoor.
Alcaraz had opted not to play in the Chinese city after battling through an ankle injury to win the Japan Open title earlier this week, and Sinner's loss means the door has opened for the rest of the field, including Australian star Alex de Minaur
Among those hoping to take advantage will be Novak Djokovic, who also struggled in the conditions but hung tough to claim a 4-6 7-5 6-3 triumph over German qualifier Yannick Hanfmann.
World No.5 Djokovic, playing in his first tournament since the US Open, was on court for two hours and 45 minutes and appeared to vomit during a changeover in the second set.
The Serbian said on court: "It's the same for every player out on the court, but it's brutal.Â
"It's brutal when you have over 80 per cent of humidity day after day, particularly for the guys when they're playing during the day with heat, with sun, it's even more brutal.
"For me, biologically, it's a bit more challenging to deal with it, but I had to really weather the storm today. Yannick played an incredible match from the beginning."
Giovanni Mpetshi Perricard produced the shock of the day earlier with a 6-4 7-5 success over fifth seed Taylor Fritz.
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