The 39-year-old is out of the US Open after a first-round defeat to Mariano Navone on Sunday night, losing 7-6 (7-5) 5-7 4-6 6-2 6-1 in a five-set marathon that lasted four hours and 36 minutes.
It was the longest opening match of a grand slam in Djokovic's career and became his earliest exit in one in two decades, dating to the 2006 Australian Open.
"It was obvious that it was an awful feeling on the court for me," said Djokovic, who was in tears at the end of the match.
"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 starts to collapse, basically cramping and pain.
"Yeah, the back just gave up in the end, and shoulder. I couldn't close it out. I was a break up in the fourth, but just struggled all the way since the fourth game of the match."
With this defeat, 21 years to the day of his US Open debut, the question now lingers as to whether this was Djokovic's final match at this or any grand slam.
Djokovic made 70 unforced errors in a painful performance that ended mere minutes before midnight.
The record holder with 24 major titles threw up at least once and later appeared to be cramping when he grabbed at his left foot.
Djokovic swallowed pills brought to him by a doctor and had his lower back massaged during a medical timeout between the fourth and fifth sets, and he grimaced after several shots.
Throughout his time on court, it was clear Djokovic was not himself, and the wear and tear of sickness and soreness took its toll.
The No.4 seed from Serbia cruised to early 3-0 and 4-1 leads before blowing them and losing the first set — the first time that happened to him in the first round of the US Open since '06.
With his wife, Jelena, watching from the stands with worried looks on her face, Djokovic had moments where he looked like one of the best to play the sport. His fist pump was reserved after winning the second set, and he put his hand to his ear and gestured to the crowd for applause on the way to taking the third.
But Navone - a 25-year-old from Argentina who earlier this year won his first ATP singles title - did not go away.
After firing a shot wide in the fourth set, Djokovic landed awkwardly and dropped his racket.
Djokovic all but conceded the fourth set. But he was unable to muster enough for the what would have been his 43rd five-set victory as Navone picked up his first.
"(It) was very tough for me because you are playing with the 'GOAT' on this court," said Navone, who idolised Djokovic growing up. "For sure it's the best thing I've had on court. It's amazing, the way we play. I mean, five sets. ... I'm very happy. I don't know. What can I say?"
Earlier, former champion Daniil Medvedev made light work of France's Hugo Gaston 6-4 6-2 6-4, exorcising the demons of his ill-fated campaign a year ago with an aggressive performance at Arthur Ashe Stadium.
A frequent - and gleeful - villain at the tournament he won in 2021, Medvedev crashed out in the opening round in 2025 but the seventh seed was all business this time around with 34 winners against just 11 from his opponent.
Czech Jiri Lehecka started his campaign with a 6-1 7-6 4-6 6-2 win over Spain's Pablo Carreno Busta on the Grandstand court.
Shortly before the tournament started, former champion Marin Cilic and 2022 runner-up Casper Ruud pulled out due to injuries.
They joined a growing list of withdrawals with the likes of Jannik Sinner, Jack Draper, Joao Fonseca and Holger Rune all missing the US Open this year.
- with Reuters
