Novak Djokovic made his earliest exit at a Grand Slam in more than two decades as the Serb succumbed to injury and illness in a shock first-round defeat by unseeded Argentine Mariano Navone at the US Open on Sunday.

The 39-year-old had arrived at Flushing Meadows with the aim of winning a fifth title and a record 25th major crown overall but crashed out 7-6(5) 5-7 4-6 6-2 6-1 to send shockwaves through the final Grand Slam of the year.

"It's something that I've been carrying, unfortunately, pretty much every match this year. Vomiting, throwing up, a serious issue there. Then my whole body started to collapse, basically cramping and pain.

"The back just gave up in the end and shoulder, and I couldn't close it out. Can the issue be fixed? I don't know. I'm trying, man. I'm trying. Let's see."

Ailing form

The last time Djokovic lost in the first round of a Grand Slam was at the Australian Open in 2006 and the Serb did not go down without a fight despite battling shoulder and back problems and vomiting midway through the match.

"I pretty much despised every moment I spent on the court for that," Djokovic told reporters.

With world number one Jannik Sinner absent and defending champion Carlos Alcaraz returning after a lengthy spell out injured, Djokovic looked primed for a run at a record 25th Grand Slam.

But Navone had not read the script and completed the biggest win of his career against his idol at Arthur Ashe Stadium.

"I was 0-3 down, feeling a bit nervous out of respect for the star I was up against," the world number 49 told ESPN.

"It's tough to play against Novak, he's an idol. He never looked particularly comfortable with his shots or physically, that's the truth."