Novak Djokovic’s US Open run came to a surprising end on Sunday night.

Djokovic — the No. 1 player in the world and the tournament’s defending champion — suddenly retired during the third set of his fourth-round match against Switzerland’s Stan Wawrinka at Arthur Ashe Stadium in New York due to a left shoulder injury.

Wawrinka, the No. 23 seed, had grabbed an early lead when Djokovic called the match. Wawrinka had won the first two sets 6-4 and 7-5, respectively, and was up 2-1 early in the third set when Djokovic approached the net, clearly ready to be done.

“Very frustrating,” Djokovic said,via the New York Times. “Obviously not the first, not the last player to get injured and to withdraw from one of the biggest events in sport. But obviously, I just came off the court, so of course it hurts.”

Djokovic was met with a mix of applause and boos as he walked off the court too, and gave a thumbs up to the crowd before entering the tunnel.

“Look, I’m not being offended by, you know, mistreated by anybody,” Djokovic said when asked about the crowd reaction, via the New York Times. “I don’t really pay too much attention on that. You know, I like to respect others. I hope that others can respect me and my decision.

“I’m sorry for the crowd. Obviously they came to see a full match, and just wasn’t to be. That’s all it is. I mean, a lot of people didn’t know what’s happening, so you cannot blame them.”

Djokovic had battled through pain in his left shoulder during his first three rounds at the US Open, too, especially in his second-round match with Juan Ignacio Londero.

The 16-time Grand Slam winner was clearly in pain throughout the match on Sunday night, too, and had 35 unforced errors before he opted not to continue. Wawrinka won 84 percent of his points on the first serve and broke Djokovic’s serve four times in the win, too.

Djokovic’s loss marked the first time he had been eliminated before the semifinal round of the US Open since 2006 — when he was just 19. He had won 36 of his past 37 Grand Slam matches and four of the last five major titles, too.

“It’s never the way you want to finish a match,” Wawrinka said on the court after the win. “I’m really sorry for Novak. He’s a good friend, an amazing champion.”

Wawrinka will now take on Russia’s Daniil Medvedev in the quarterfinals. The three-time Grand Slam winner has rallied back this season after plummeting to No. 263 in the world in 2018. He entered the year back up at No. 66 in the rankings, and reached the quarterfinals of the French Open earlier this year.

More from Yahoo Sports:

• Forde’s 10 Takeaways: Did Vols or ‘Noles have worse Week 1?

• Thamel: How Cristobal blew Oregon’s shot at beating Auburn

• Source: McCoy agrees to 1-year deal with Chiefs

• Twins break single-season home run record with month to play