NEW YORK — Defending champion Novak Djokovic was just as surprised as Carlos Alcaraz at the US Open, losing 6-4, 6-4, 2-6, 6-4 to 28th-seeded Australian Alexei Popyrin in the third round on Friday night.

The second-seeded Djokovic was attempting to become the first player in tennis history to win 25 Grand Slam singles titles. Instead, following knee surgery in June, he ends a year without claiming at least one major championship for the first time since 2017. That hadn’t happened since 2010.

Also of note: 2024 will be the first season since 2002 in which none of the three Great Tennis Men – Djokovic, Rafael Nadal and Roger Federer – have won a Grand Slam trophy.

The third-round exit is Djokovic’s worst performance at Flushing Meadows; the only other times he was defeated so early at the US Open were in 2005 and 2006. The man Djokovic defeated 18 years ago, International Tennis Hall of Fame member Lleyton Hewitt, now captains Australia in the Davis Cup and was sitting in Popyrin’s guest box at Arthur Ashe Stadium.

It is Djokovic’s first defeat at a major tournament since the 2017 Australian Open, where he lost in the second round to Denis Istomin.

The 37-year-old Djokovic has reached the final in Ashe ten times, winning the title in 2011, 2015, 2018 and 2023.

On Friday, however, he made 14 double faults and looked physically slow and emotionally flat, perhaps still feeling tired after winning Serbia’s first Olympic gold medal earlier in August by beating Alcaraz in the final of the Paris Olympics.

The third-seeded Alcaraz entered the US Open as a pre-tournament favorite, having won the French Open and Wimbledon. He admitted his energy was lower than he realized after being knocked out by 74th-seeded Botic Van De Zandschulp 6-1, 7-5, 6-4 in New York on Thursday night.

For the 25-year-old Popyrin this meant a real breakthrough: he had won 0-3 against Djokovic and 0-6 in the third round of the majors.

But the powerful Popyrin is still playing as well as ever. Less than three weeks ago, he won the biggest title of his career at a hardcourt tournament in Montreal, where he won five times against opponents ranked in the top 20.

Everything was against Djokovic, who did not perform at his usual level.

Popyrin was superb at the net, taking 10 out of 10 serve-and-volleys and winning 25 of the 36 points overall when he pushed forward. Djokovic, on the other hand, won the point on only 19 of his 40 trips to the net, partly because Popyrin kept throwing passing shots past him.

Popyrin made big cuts with his powerful forehand and achieved 22 of his total 50 winning hits with that stroke.

And he broke Djokovic five times, including a 3-2 lead in the fourth. That game felt huge, lasting more than 10 minutes and featuring four break chances for Popyrin, who converted the last with an inside-out forehand to cap a 22-shot exchange, then fell back on his heels, clenched both fists and let out a howler. He also took Djokovic’s next service game, to make it 5-2.

The first time Popyrin served for the match, he faltered, allowing Djokovic to break. The second time, Popyrin sealed the deal, holding at love when Djokovic sent a forehand long.

Popyrin will now attempt to reach his first Grand Slam quarterfinal by beating No. 20 Frances Tiafoe, who won 4-6, 7-5, 6-7(5), 6-4, 6-3 over No. 13 Ben Shelton on Friday in a match between two Americans.

The Associated Press contributed to this report.