NEW YORK — Novak Djokovic grinded through physical and internal ailments, made one mistake after another and could not find what it took to beat a feisty, younger opponent who was not intimidated under the lights against tennis’ most decorated player.

The 39-year-old is out of the U.S. Open after a first-round defeat to Mariano Navone on Sunday night, losing 7-6 (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. He had never lost in the first round at the U.S. Open.

“I didn’t enjoy myself,” Djokovic said. “I think it was obvious that it was an awful feeling on the court for me.”

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.

Djokovic made 70 unforced errors in a painful performance that ended mere minutes before midnight.

“It’s something that I’ve been carrying, unfortunately, pretty much every match this year: vomiting, throwing up, a serious issue there,” Djokovic said. “Then my whole body starts to collapse, basically cramping and pain. Yeah, the back just gave up in the end and shoulder, and I couldn’t close it out.”

With this defeat, 21 years to the day of his U.S. Open debut, the question now lingers as to whether this was Djokovic’s final match at this or any Grand Slam. After the loss, he said he was “trying to address really what’s going on and how far I can go this way.”

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 U.S. Open since ’06.

“Just struggled all the way since the fourth game of the match,” Djokovic said. “When it comes to match itself and overall feeling of how I felt with body and playing, it was really not enjoyable. I pretty much despised every moment that I spent on the court for that.

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.

Neither did the frustration of not being healthy or at his best. 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 what would have been his 43rd five-set victory as Navone picked up his first, calling it a dream come true.

“(It) was very tough for me because you are playing with the ‘GOAT’ on this court,” said Navone, who idolized Djokovic growing up. “For sure it’s the best thing I’ve had on court. This is an amazing court and the biggest stage. It’s amazing, the way we play. I mean, five sets. … I’m very happy. I don’t know. What can I say?”

It extended a nightmare stretch for Djokovic, who also lost in the first round at the hardcourt tuneup in Cincinnati earlier this month. That was his first action since losing to top-ranked Jannik Sinner in the semifinals at Wimbledon.

Djokovic expressed hope Saturday that his early exit at Cincinnati gave him more time to prepare for the U.S. Open but acknowledged concern that the first match at any tournament has become challenging for him in recent years. Instead of overcoming the hurdle and building from there, he is left to contemplate an uncertain future.