Fritz had not dropped a set in the previous two rounds and looked to be among the prime contenders to end a 23-year U.S. men's major drought but Cerundolo brought his best level to reach the fourth round of the U.S. Open for the first time.
He next plays either Belgian Alexander Blockx or Italian Flavio Cobolli.
"He was playing way better than me the first two sets," said Cerundolo, who played on Arthur Ashe Stadium for the first time. "I started getting into it step by step and I think fourth and fifth I played really good tennis. I wasn't finding that tennis in the previous sets, previous rounds."
Fritz had cruised through his second-round match in little more than 90 minutes and looked well on his way to another smooth victory, saving 11 of the 13 break points he faced in the opening two sets.
But after trading breaks early in the third set, the Argentine dug in his heels, and the 2024 runner-up looked exasperated when he hit a wonky shot beyond the baseline on break point in the sixth game.
Cerundolo upped his level as Fritz struggled with uncharacteristic mistakes in the fourth set and the American smacked his racket against his thigh after sending another shot long on break point in the fifth game.
The Argentine made his opponent sprint back and forth along the baseline with a series of powerful precision shots in the ninth game of the final set, where Fritz's shoelace snapped as he was serving at 15-40 down.
The brief interruption did nothing to break Cerundolo's stride and Fritz whacked the ball into the net to gift his opponent the break on the next point. The Argentine sealed the win with a fine backhand strike.
