Novak Djokovic's latest bid for a record 25th Grand Slam title crashed to a halt on Friday as 28th-ranked Alexei Popyrin knocked the defending champion out of the US Open third round.

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.

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

"It was just an awful match for me," Djokovic said, adding that he would now try to "recalibrate and look forward."

Popyrin, coming off the biggest title of his career at the Montreal Masters, seized the first two sets with a fearless display on serve and from the baseline.

Djokovic gave himself some breathing room with an early break in the third. Popyrin clawed back the break only for Djokovic to break him twice more, the Serbian taking full advantage of Popyrin's mounting errors.

But the Aussie responded in a tense fourth set, saving break points in the second game before seizing a break 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.

After saving a pair of break points in the next game, the Aussie broke again for a 5-2 lead.

Djokovic, not about to go quietly, won two straight games to cut the gap but Popyrin claimed the match with a love game as Djokovic fired one more forehand long.

"We had some battles at the Australian Open and Wimbledon," Popyrin said. "This match was a little different. I was able to take my chances when I had them.

"To be in the fourth round of a Grand Slam by beating the greatest of all time is unbelievable," Popyrin said.

He 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.

That included one break in each of the last two sets.

When Tiafoe closed it out after an intense four hours and three minutes, he spread his arms to the roaring crowd before meeting his good friend Shelton for a lengthy hug at the net.

World number six Andrey Rublev of Russia beat Czech Jiri Lehecka 6-3, 7-5, 6-4 to line up a meeting with Grigor Dimitrov, a 6-3, 6-3, 6-1 winner over Tallon Griekspoor.

Eighth-seeded Norwegian Casper Ruud rallied from two sets down to beat 19-year-old Shang Juncheng of China 6-7 (1/7), 3-6, 6-0, 6-3, 6-1 to book a meeting with American Taylor Fritz, a 6-3, 6-4, 6-2 winner over Argentina's Francisco Comesana.

- Gauff rallies -

Defending women's champion Coco Gauff survived late-match drama in a 3-6, 6-3, 6-3 victory over Elina Svitolina.

Gauff's third-set surge had carried her to triple match point at 5-2, but she delivered a pair of double faults and Svitolina saved another with a blazing backhand on the way to a break.

But Gauff broke Svitolina at love in the next game to lock up the win.

Gauff next faces fellow American Emma Navarro, who upset her in the fourth round at Wimbledon. Navarro beat Ukraine's Marta Kostyuk 6-4, 4-6, 6-3.

Second-seeded Australian Open champion Aryna Sabalenka closed out the night session, taking on Russian Ekaterina Alexandrova.

Seventh-seeded Olympic gold medallist Zheng Qinwen of China, who rallied from a set down in each of her first two matches, dispatched Germany's Jule Niemeier 6-2, 6-1.

Zheng next faces Croatian Donna Vekic in a rematch of the Paris Olympics gold medal match.

Spain's Paula Badosa saved a match point en route to a 4-6, 6-1, 7-6 (10/8) victory over Romanian qualifier Elena-Gabriela Ruse, who had toppled Wimbledon champion Barbora Krejcikova in the second round.