One day after third seed Carlos Alcaraz slumped to a shock defeat against 74th-ranked Botic van de Zandschulp, 25-year-old Popyrin robbed the tournament of another superstar with a 6-4, 6-4, 2-6, 6-4 victory.

Popyrin handed Djokovic his earliest US Open exit in 18 years and his earliest Grand Slam exit since he fell in the second round of the Australian Open in 2017 -- which was also the last year the Serbian great failed to claim a single Grand Slam title.

Although he won the Olympic gold he had long coveted at the Paris Games, an uneven season that included knee surgery saw Djokovic come up empty in the majors. Djokovic later said that reaching the third round was "a success" given his current poor form and pointed to the efforts dedicated to achieving the Golden Slam. 

He had beaten Popyrin in three prior encounters, including at the Australian Open and Wimbledon this year. However, a career-high 14 double faults -- 49 unforced errors total -- were too much for Djokovic to overcome.

"It was just an awful match for me," Djokovic said. "I mean, I tried so many things, and sometimes that's an issue ... you move away from the basics that work. You lose the foundation. You lose the movement, the timing, the rhythm, the tempo, everything, whether it's a serve or any other shot."

Popyrin, coming off the biggest title of his career at the Montreal Masters, saved five break points in the sixth game of the match, swinging fearlessly to seize the first two sets. Djokovic gave himself some breathing room with an early break in the third. Popyrin clawed back only for Djokovic to break him twice more, the Serbian taking full advantage of Popyrin's mounting errors.

However, the Aussie responded in a tense fourth set, saving break points in the second game before breaking again for a 3-2 lead. He stayed patient as Djokovic saved three break points and when the Serbian double-faulted to gift him another Popyrin capitalized with a blistering forehand winner and let out a massive roar.

Djokovic delivered four double faults in dropping his serve to trail 5-2. He won the next two games, but Popyrin claimed the match with a love game.

"I was waiting for him to kind of step up," Popyrin said. "I didn't want to be one of those moments where Novak kind of stepped up and came back from two sets to love down. It was kind of extra motivation for me not to do that and to win that fourth set."

Popyrin will next face Frances Tiafoe, who beat fellow American Ben Shelton 4-6, 7-5, 6-7 (5/7), 6-4, 6-3 in a pulsating afternoon contest on Arthur Ashe Stadium. Tiafoe avenged a quarter-final loss to Shelton in New York last year, withstanding 23 aces with a brilliant return display that saw him muster 21 break points and convert five.