The 37-year-old Djokovic, who has won the US Open four times, was frustratingly unsuccessful in his attempt to earn a record 25th Grand Slam championship, falling to the 28th-ranked Australian 4-6, 4-6, 6-2, 4-6, as per AFP.
He made an unusual 14 double faults and 49 unforced errors in his defeat, which means that he will finish the season without a Grand Slam victory for the first time since 2017.
The latest crushing setback for Djokovic 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.
After defeating him in the semifinals of the Australian Open, Sinner went on to overtake Djokovic for the world number one ranking, which he had held for a total of 428 weeks.
On the eve of his quarterfinal match at the French Open, Djokovic had to retire due to a knee injury that needed surgery.
His comeback was unable to stop Alcaraz from winning a seventh Wimbledon.
Due to Friday’s incredible outcome, none of the Slams will have been won by any of the “Big Three” – Roger Federer, Novak Djokovic, and absent Rafael Nadal-for the first time since 2002.
Following Alcaraz’s shocking defeat in the second round on Thursday, the Serb’s withdrawal on Friday dealt the US Open yet another blow.
“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.”
Djokovic’s victory at the Olympics in Paris earlier in August was his only solace in an otherwise disappointing year.
Being only the sixth player to complete the Golden Slam of four majors and Olympic gold, he called his emotionally charged victory over Alcaraz his “greatest achievement”.
That title, the 99th of his career, might prove to be his final career-defining achievement.
He would be the oldest male Grand Slam winner of the modern era if he continued to play into 2025 and won an 11th Australian Open championship in January.
Djokovic, who is 12 years elder than Popyrin, paid a high price on Friday when he was unable to convert five break points in the sixth game of the opening set.
In the ninth game, the Australian had no such issues, converting one break point before serving it out with confidence to win the opening set.
Popyrin arrived in New York with confidence after winning his first Masters title in Montreal, despite losing to Djokovic in the Australian Open and Wimbledon this year.
His assurance on the hard court was evident when he broke for 3-2 in the second set, then backed it up for 4-2 and won the set with a self-assured serve and volley.
But in the third set, Djokovic used all of his recuperative might to even the score with two breaks of his own.
In the fourth game, q fired-up Popyrin took the lead 3-2 thanks to a serve break achieved with a free-swinging forehand and a thunderous shout that echoed throughout the enormous Arthur Ashe Stadium.
Popyrin quickly had a double break lead, but Djokovic managed to hold on and win one break.
Popyrin, however, was unstoppable as he achieved a historic triumph and possibly signaled Djokovic’s end.
