Djokovic was knocked out of the tournament by Argentina’s Mariano Navone, who gave the Serbian legend few opportunities to fight his way back into the match.
In a dramatic and physically demanding clash, Djokovic appeared to struggle physically and was even seen vomiting into a towel bin during the match.
The 24-time Grand Slam champion eventually bowed out after Navone prevailed 7-6 (7-5), 5-7, 4-6, 6-2, 6-1.
The defeat marked the first time Djokovic had been eliminated in the opening round of the US Open.
Reflecting on the difficult match, Djokovic was quoted by the BBC as saying: "I think it was obvious that it was an awful feeling on the court for me."
"I don't want to take too much out of Mariano's win. Congrats to him, he's a nice guy and a fighter - but I didn't enjoy myself," he added.