Novak Djokovic slumped to his earliest exit at the US Open in 18 years on Friday as a four-set, third round defeat to Alexei Popyrin sparked more questions over his long term future in the sport.

The 37-year-old Djokovic, a four-time champion in New York, lost 6-4, 6-4, 2-6, 6-4 to the 28th-ranked Australian, leaving him frustratingly short once again of winning a record 25th Grand Slam title.

His defeat, which saw him hit an uncharacteristic 14 double faults and commit 49 unforced errors, means that for the first time since 2017 he will end the season without a Grand Slam title.

The latest crushing setback comes in a year which saw Jannik Sinner succeed him as Australian Open champion before Carlos Alcaraz took his French Open crown and swept him off court in the Wimbledon final.

Having defeated him in the Australian Open semi-finals, Sinner went on to also take his world number one ranking which Djokovic had held for a combined 428 weeks.

A knee injury, which required surgery, forced Djokovic to withdraw from the French Open on the eve of his quarter-final.

His recovery still wasn't strong enough to prevent Alcaraz from claiming an eighth Wimbledon.

Friday's stunning result means that for the first time since 2002, none of the Slams will have been won by any members of the 'Big Three' of Djokovic, the absent Rafael Nadal or the retired Roger Federer.

The Serb's exit on Friday was another bodyblow to the US Open after Alcaraz was shocked in the second round on Thursday.

"I played some good tennis," said Popyrin, who was watched in his player's box by Lleyton Hewitt, the man who stunned Djokovic in the third round in New York in 2006.

"To be in the fourth round of a Grand Slam by beating the greatest of all time is unbelievable."

The only consolation for Djokovic in a frustrating year was winning Olympic gold in Paris earlier in August.

Olympic gold

He described that emotion-fuelled victory over Alcaraz as his "greatest achievement" as he became just the sixth player to complete the Golden Slam of four majors and Olympic gold.

That title -- the 99th of his career -- may turn out to be his last defining moment in the sun.

If he were to keep playing into 2025 and secure an 11th Australian Open crown in January, he would be the oldest male Grand Slam champion of the modern era.

On Friday, Djokovic paid a heavy price for failing to convert five break points in the sixth game of the opening set against Popyrin, 12 years his junior.

The Australian had no such trouble in the ninth game converting a single break point before confidently serving it out to take the first set.

Popyrin had lost to Djokovic at the Australian Open and Wimbledon this year but arrived in New York buoyed by capturing his first Masters title in Montreal.

That hardcourt confidence shone through as he broke for 3-2 in the second set, backing it up for 4-2 and pocketing the set with a confident serve and volley.

However, Djokovic called on all his powers of recovery to cut the deficit with two breaks of his own in the third set.

A fired-up Popyrin edged ahead 3-2 in the fourth, a break of serve secured with a free-swinging forehand and accompanied by a chilling roar which bounced around the cavernous Arthur Ashe Stadium.

Popyrin raced double break ahead before Djokovic clung on to retrieve one break.

But Popyrin was not to be denied as he sealed a famous victory for him and marked potentially the point of no return for Djokovic.