NEW YORK — Novak Djokovic suffered a major upset at the hands of Alexei Popyrin with a 6-4, 6-4, 2-6, 6-4 beating in the third round of the US Open on Friday to end the Serbian's bid for a 25th Grand Slam title.

Djokovic, who had to dig deep to win the Olympic gold medal in Paris this month, looked sluggish against the energized Australian, who notched the biggest win of his career.

"I spent a lot of energy winning the gold, and I did arrive to New York just not feeling fresh mentally and physically," Djokovic told reporters.

"But because it's US Open, I gave it a shot and I tried my best. I didn't have any physical issues. I just felt out of gas and you could see that with the way I played."

Popyrin, who lost to Djokovic at both the Australian Open and Wimbledon this year, raised his arms in triumph and beamed a wide smile after knocking out the tournament's defending champion to reach the round of 16 of a major for the first time.

"Third time lucky I guess," Popyrin said in an on-court interview.

"No, honestly we had some battles at the Australian Open and Wimbledon. I had my chances in those matches but didn't take them. This match was a little bit different, I was able to take my chances when I had them and played some good tennis."

Djokovic had five break point chances in the opener but failed to convert any of them, while Popyrin broke serve on his first opportunity for a 5-4 lead en route to grabbing the first set.

Popyrin broke again in the second when Djokovic's volley landed wide for a 3-2 advantage and took control of the match with a perfectly executed serve and volley to capture the second set.

Djokovic showed some life in the third, when the second seed broke serve with a forehand that Popyrin could not handle and took the set to claw his way back into the match.

But the comeback proved short-lived, with Popyrin letting out a mighty roar when he crushed a ferocious forehand winner for a break of serve and 3-2 lead in the fourth. He completed the upset when Djokovic's forehand sailed long on match point.

The veteran Djokovic was uncharacteristically sloppy in the contest, issuing 14 double faults, a record for him in a Grand Slam match, while his 25-year-old opponent smacked 50 winners.

"If you play on a quick surface like this without the serve, without ability to win free points there, very low first-serve percentage, many double faults, then you can't win," Djokovic said.

"It was just an awful match for me."

The loss means Djokovic will end the season without a Grand Slam title for the first time since 2017.

The upset on Arthur Ashe Stadium came one night after third seed and tournament favorite Carlos Alcaraz, who finished runner up to Djokovic at the Paris Games, was stunned in straight sets by unseeded Dutchman Botic van de Zandschulp.

Next up for Popyrin is a fourth-round meeting with American Frances Tiafoe.