Alexei Popyrin has claimed the biggest win of his career, defeating Novak Djokovic in four sets to move into the US Open fourth round for the first time.

Popyrin, the 28th seed, was given little chance against the legendary Djokovic but mixed patience and power to stun the four-time New York champion in the 6-4, 6-4, 2-6, 6-4 victory.

The win is the second massive upset at Flushing Meadows in as many days, with top seed Carlos Alcaraz eliminated by unseeded Dutchman Botic van de Zandschulp on Friday.

Popyrin will now face American Frances Tiafoe on Monday for a place in the quarterfinals.

"Third time lucky I guess. We've had some battles at the Australian Open and Wimbledon. I had some chances and those matches and didn't take them, and this time I was able to take my chances," Popyrin said after the match.

"It's unbelievable because I've been in the third round about 15 times and I haven't been able to get to the fourth.

"To be able to do it against the greatest of all time is unbelievable.

"The hard work paid off."

While Djokovic was gripped with serving yips, the ice-cool Sydneysider was rock solid on his delivery, fending off seven of eight break points he faced during a tension-marred fourth — and ultimately — deciding set.

Djokovic dropped serve five times and coughed up another extraordinary 14 double-faults to take his tournament tally to a shocking 32 in eight-and-a-bit sets including a second-round retirement from fellow Serb Laslo Djere.

Fittingly, Davis Cup captain Lleyton Hewitt was in Popyrin's courtside box for the biggest win of the former French Open junior champion's career.

Not since Hewitt in the US Open third round in 2006, when Djokovic was only 19, had an Australian conquered the longest-serving world number one in tennis history.

Popyrin entered the Open seeded at a slam for the first time after also becoming the first Australian since Hewitt in 2003 to win an ATP 1000 crown.

But few could have predicted the clinical manner in which the Montreal Masters champ dismantled Djokovic.

In a huge turning point, Popyrin held serve from 0-40 in the sixth game of the opening set before breaking Djokovic at 4-4 and closing out the set to love.

The gritty underdog shrugged off the disappointment of not nabbing another break in the first game of the second set when Djokovic dished out three double-faults.

Popyrin patiently waited for another chance, and took it with a sizzling forehand pass to break for 5-3 and then seize a commanding two-sets-to-love advantage.

Djokovic had battled back from two sets down eight previous times in his unparalleled career and threatened to once more after taking the third in champion's style.

But there was no ninth life for Novak when Popyrin refused to blink under the intense pressure and cashed in on five double-faults from Djokovic in one decisive game.

ABC/AAP