NEW YORK — Defending champion Novak Djokovic was shocked at the US Open one night after Carlos Alcaraz was, bowing out in the third round with a 6-4, 6-4, 2-6, 6-4 loss to 28th-seeded Alexei Popyrin of Australia on Friday night.

The No. 2-seeded Djokovic was trying to become the first player in tennis history with 25 Grand Slam singles titles. Instead, after knee surgery in June, he finishes a year without claiming at least one major championship for the first time since 2017. Before that, it hadn’t happened since 2010.

Also of note: 2024 now becomes the first season since 2002 in which none of the Big Three of men’s tennis — Djokovic, Rafael Nadal and Roger Federer — earned a Slam trophy.

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

It’s Djokovic’s earliest loss at a major since the 2017 Australian Open, where he lost in the second round to Denis Istomin.

Djokovic, who is 37, has reached the final in Ashe 10 times, leaving with the title in 2011, 2015, 2018 and 2023.

On Friday, though, he double-faulted 14 times and looked physically sluggish and emotionally flat, perhaps residual fatigue after collecting his first Olympic gold medal for Serbia by beating Alcaraz in the final at the Paris Games earlier in August.

The No. 3-seeded Alcaraz entered the US Open as the tournament favorite having won the French Open and Wimbledon, and acknowledged his energy was lower than he realized after getting eliminated in New York by 74th-ranked Botic Van De Zandschulp 6-1, 7-5, 6-4 on Thursday night.

For the 25-year-old Popyrin, this represented a real breakthrough: He had been 0-3 against Djokovic and 0-6 in third-round matches at majors.

But the strong-serving Popyrin is playing as well as ever, coming off the biggest title of his career less than three weeks ago at a hard-court tournament in Montreal, where he picked up five wins against opponents ranked in the top 20.

Everything was working against Djokovic, who was not up to his usual high standards.

Popyrin was terrific at the net, going 10 for 10 on serve-and-volley approaches and 25 for 36 overall on points when he pushed forward. Djokovic, in contrast, only won the point on 19 of his 40 trips to the net, in part because Popyrin kept flipping passing shots by him.

Popyrin took big cuts with his powerful forehand, accumulating 22 of his 50 total winners with that shot.

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

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

Now Popyrin will try to reach his first Grand Slam quarterfinal by getting past No. 20 Frances Tiafoe, who advanced Friday with a 4-6, 7-5, 6-7 (5), 6-4, 6-3 win over No. 13 Ben Shelton in a matchup between two Americans.

The Associated Press contributed to this report.