Ninth seed Fritz had not dropped a set in the previous two rounds and looked to be among the prime contenders to end a 23-year US men's major drought, but Cerundolo brought his best level on Saturday (local time) to rally from two sets and a break down and reach the fourth round of the Open for the first time.
"I don't know how I let that happen today," 2024 runner-up Fritz told reporters at his post-match press conference.
Cerundolo, who played on Arthur Ashe Stadium for the first time, next faces Belgian Alexander Blockx, who upset fifth-seeded Italian Flavio Cobolli 6-7 6-3 6-0 6-3.
"I started getting into it step by step and I think fourth and fifth I played really good tennis,'' the Argentine said.
Fritz joined the casualties among the men's pre-tournament favourites, with only four of the top 10 seeds left in the draw - No.1 Alexander Zverev, No.2 Carlos Alcaraz, No.7 Daniil Medvedev and No.8 Ben Shelton.
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.
After trading breaks early in the third set, the Argentine dug in his heels, and Fritz looked exasperated when he hit a 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 racquet 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 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.
In late action, top seed Zverev secured a 6-2 7-6 (7-2) 6-2 victory over Chile's Alejandro Tabilo to reach the fourth round.
After spending nine hours and 26 minutes on court across back-to-back five-setters against Lorenzo Sonego and Quentin Halys, the last thing the German would have wanted was another long night on Arthur Ashe Stadium.
"My coach was quite smart, he said that best-of-five sets doesn't mean that you have to play five sets. I didn't know it until now, that was quite helpful," Zverev joked later.
The 29-year-old is having a fantastic year, having won his first grand slam title at the French Open, before finishing runner-up at Wimbledon.
American 14th seed Learner Tien edged Czech 17th seed Jakub Mensik 6-3 1-6 6-7 (2-7) 6-3 6-4 to reach the round of 16 in New York for the first time.
