Djokovic, whose last first round defeat at a grand slam came in the 2006 Australian Open, went up two sets to one and a break in the fourth set against Navone. However, he was unable to close it out against the world number 49, who won 11 of the last 12 service games to complete the upset.

The 39-year-old vomited ‌midway through the match and was hampered by back and shoulder issues that affected his serve towards the end.

"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. Again, I don't want to take too much out of ​his win.

"Congratulations to him. He's a nice guy, a fighter. But I didn't enjoy myself."

Navone revelled in the biggest win of his career and was stunned to have beaten ​a player he considers the greatest of all time (GOAT).

"Five sets, against the GOAT, it's not something you do every day. I'm very happy," Navone said on court.

"It means a lot to me. ⁠It's a dream come true. Now ​I have to recover. It's almost 12 a.m. We have to go to sleep."

He later told ESPN he was still trying to come to terms with what he had achieved.

"It'll take a while for the adrenaline to settle down," Navone added. "I've only just picked up my phone and it won't ‌stop ringing.

"I imagine there must be quite a commotion back at home."

Didn't want to give up

Djokovic had arrived for his 20th appearance at the Grand Slam with questions over his form and fitness after losing to Thiago Agustin Tirante in his Cincinnati opener two weeks ago.

The first set went Navone's way as he held his nerve in a tiebreak. Both players broke the other once each, with Djokovic even holding a mini-break during the tiebreak. Yet, the Argentinian won the final two points to claim the opening set in 75 minutes.

Djokovic, seeded fourth for the tournament, responded by winning the next two sets. He broke Navone's serve in the penultimate game of both sets to go up two sets to one.

Djokovic struggled in the third set, throwing up on a couple of occasions as he struggled on court. Taking a 2-1 lead in the fourth set, he could not keep up the level needed to get over the line.

Navone proceeded to break the Serb right back before winning the next four games to force a fifth set. Losing the first three games of the deciding set, Djokovic wiped tears from his eyes as he won what would be the last game before his opponent finished off the match.

With the result, Navone moves on to face the winner of Matteo Berrettini and Stan Wawrinka in the next round.

For Djokovic, who had 70 unforced errors in the match, the defeat marked his earliest-ever exit in Flushing Meadows. He will finish the year without a grand slam title for the third consecutive year.

Since his first major win in 2008, he had previously never gone more than two straight years without a slam victory.

"I didn't want to give up in fourth ⁠or fifth," Djokovic said when asked if the ⁠thought of quitting crossed his mind.

"I wanted ‌to finish the match."