Djokovic’s defeat ends his bid to complete the calendar Grand Slam and surpass Roger Federer and Rafael Nadal with a 21st major title.
He remains tied with Federer and Nadal on 20 Grand Slam titles each, with the trio locked in a battle to finish their careers with the most major titles.
Popyrin, who hit 24 aces and 45 winners, will face either American Jenson Brooksby or Marton Fucsovics of Hungary in the fourth round.
The Australian said after the match: “I’m just glad I came out on top. It was a tough match. I’m just glad I could just play a really good level and come out with the win.”
Despite the loss, Djokovic remains one of the greatest tennis players of all time and will go down in history as one of the sport’s legends.
It was just an awful match from me. Djokovic, who had to dig deep to win the Olympic gold medal against Alcaraz earlier this month, failed to convert five break point opportunities in the opening set, while Popyrin broke serve on his first chance for a 5-4 lead and then grabbed the first set.
Popyrin broke again when Djokovic’s forehand volley landed wide for a 3-2 advantage and he soon took control of the match with a perfectly executed serve and volley to capture the second set.
The second-seeded Djokovic showed some life in the third to claw his way back into the match.
But the comeback proved short-lived, with Popyrin letting out a mighty roar when he crushed a ferocious forehand winner for a break of serve and 3-2 lead in the fourth.
He completed the upset when Djokovic’s forehand sailed long on match point.
The last time Djokovic did not taste Grand Slam glory in a season was in 2017 as he suffered his earliest loss at Flushing Meadows since 2006.
Third time lucky [this year] I guess, Popyrin said. Honestly, we had some battles at the Australian Open and Wimbledon. I had my chances in those matches, but didn’t take them. This match was a little different. I was able to take my chances when I had them and played some good tennis.
It’s unbelievable because I’ve been in the third round about 15 times in my career, but I haven’t been able to get past to the fourth round.
To be able to do it against the greatest of all time to get into the fourth round is unbelievable.