Popyrin enjoyed a positive build-up to the US Open, claiming his maiden ATP Masters 1000 title in Montreal earlier this month.

The Sydney-born player was brimming with confidence as he manoeuvred his way through the first set, fending off five break points before striking at 4-4 and serving it out.

He looked even better in the second, steadily going about his work and winning 88% of points on his first serve as Djokovic continued to falter.

The 24-time major winner finally burst to life at the beginning of the third set, winning the first three games before a blip allowed Popyrin to break back.

But Djokovic was quick to respond and animatedly demanded more noise from the lively crowd on Arthur Ashe Stadium as he restored his advantage and broke for a third time to keep his title defence alive.

Djokovic was aiming to win a fifth US Open that would have moved him past Margaret Court and take sole ownership of the all-time record for the most Grand Slam singles titles.

The pair continued to go toe-to-toe in set four, but Popyrin landed Djokovic in deep trouble when he he successfully converted his fourth break point in the fifth game.

He held firm in his next service game, too, saving two break points before a series of double faults and careless errors from the usually clinical Djokovic moved the 28th seed to the brink of a seismic victory.

With a double break behind him, Popyrin failed on his first attempt at serving out the match but he was more successful the second time around, landing three huge serves before Djokovic pushed the first match point long.

"It's unbelievable because I've been in the third round about 15 times in my career but haven't been able to get to the fourth round," Popyrin said.

"To be able to do it against the greatest of all time to get into the fourth round is unbelievable, it's a great feeling that the hard work has paid off."

Earlier, Tiafoe avenged his defeat by Shelton at last year's US Open by beating the 13th seed in an all-American five-set thriller.

The pair, who are good friends, faced each other in the quarter-finals in New York last year with Shelton emerging as the victor.

But it was the lower-ranked Tiafoe who won on Friday, coming from behind twice to triumph 4-6 7-5 6-7 (5-7) 6-4 6-3 after more than four entertaining hours on Arthur Ashe Stadium.

"Ben is an incredible player, he really is. He goes for all kinds of shots, he's got no care in the world. It's really annoying," 20th seed Tiafoe said.

Meanwhile, American 12th seed Taylor Fritz continued his perfect run in New York with a 6-3 6-4 6-2 victory against Argentina's Francisco Comesana.

Fritz, who has yet to drop a set, will face Norway's Casper Ruud, a finalist in 2022 who made a remarkable comeback from two sets down to beat Shang Juncheng of China 6-7 (1-7) 3-6 6-0 6-3 6-1.

Russian sixth seed Andrey Rublev was the first men's singles player to make it into the fourth round with an assured 6-3 7-5 6-4 victory over Czech Jiri Lehecka.

Rublev, a 10-time Grand Slam quarter-finalist who has yet to win a major, will face Grigor Dimitrov after the Bulgarian ninth seed claimed a dominant 6-3 6-3 6-1 win against Dutchman Tallon Griekspoor.

Russell Fuller, BBC tennis correspondent

The signs were clear - even in two straight-sets victories earlier in the week - that Djokovic was far from at his best, and Popyrin was a man perfectly equipped to take advantage.

Fuelled by the confidence of winning the Masters event in Montreal earlier this month, the Australian became the first man in 18 years to beat Djokovic before the fourth round of the US Open.

The 24-time Grand Slam champion served 32 double faults in just three matches.

Mentally, Djokovic was drained. The Olympic gold was his highlight of this - and many other - years, and at the age of 37 he was never likely to switch surfaces without any match practice and win seven matches over the best of five sets.

His exit means Roger Federer remains the last man to defend the US Open title - all the way back in 2008.