Images from the US Open men's singles third round matches at Flushing Meadows, New York, on Friday.

Novak Djokovic suffered a major upset at the hands of Alexei Popyrin, losing 6-4, 6-4, 2-6, 6-4 in the third round of the US Open on Friday. It ended the Serbian's bid for a 25th Grand Slam title.

Djokovic, who had to dig deep to win the Olympic gold medal in Paris this month, looked sluggish against the energized Australian, who notched the biggest win of his career to reach the Round of 16 of a major tournament for the first time.

Popyrin, who lost to Djokovic at the Australian Open and Wimbledon this year, raised his arms in triumph and beamed a wide smile after overcoming the tournament's defending champion.

"Third time lucky I guess," Popyrin said in an on-court interview.

"No, 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 bit different, I was able to take my chances when I had them and played some good tennis."

Djokovic had five break-point chances in the opening set but failed to convert any of them, while Popyrin broke serve on his first opportunity for a 5-4 lead before grabbing the first set.

Popyrin broke again in the second when Djokovic's forehand volley landed wide for a 3-2 advantage. He 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, when he broke serve with a forehand that Popyrin could not handle and took the set 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 upset on Arthur Ashe Stadium came one night after third seed and tournament favorite Carlos Alcaraz, who finished runner up to Djokovic at the Paris Games, was stunned in straight sets by unseeded Dutchman Botic van de Zandschulp.

Next up for Popyrin is a fourth round meeting with American Frances Tiafoe.

Tiafoe beats Shelton in all-American five-set epic

Frances Tiafoe weathered a Ben Shelton storm in a captivating all-American blockbuster to win 4-6, 7-5, 6-7(5), 6-4, 6-3 and move into the last-16 of the US Open on Friday.

Both players have had semi-final runs at Flushing Meadows in the past and it was the electric Tiafoe who prevailed in a four-hour battle in what was a repeat of last year's quarter-final match-up, where the younger Shelton had won in four sets.

The two players are good pals off the court but set their friendship aside and after Shelton promised a 'war', the clash lived up to its billing, bringing the crowd to its feet on several points and rallies as the match went the distance.

Shelton, who held a 2-0 head-to-head record going into the contest, fired 23 aces and 63 winners but ultimately Tiafoe exacted revenge and earned a fourth-round clash with either defending champion Novak Djokovic or Alexei Popyrin.

After Coco Gauff warmed up the crowd at Arthur Ashe Stadium with a gritty comeback win, the fans were relatively muted as the two players went through the motions in the opening set.

But they instantly came to life on a thrilling rally where the net cord brought both players scrambling to the net and Shelton eventually won the point when the referee stopped play after Tiafoe had touched the net to concede a 4-1 lead.

Shelton continued to entertain the crowd with his shots, on one occasion leaping gracefully into the air at the net for a fine backhand smash while he chased down another return to fire a cross-court forehand winner that drew collective gasps.

However, Tiafoe found a way back into the match in the second set. Although Shelton held serve from 0-40 down in two straight service games, Tiafoe finally converted a break point at 5-5 and then took the second set.

There was little to separate the two in the third set as they went into a tie-break where Shelton raced away into a 6-0 lead after Tiafoe made errors and kicked over a towel bin in disgust.

Tiafoe clawed his way back to 6-5 as Shelton nearly imploded but on his seventh set point, the unfazed American served a 143 mph ace -- the fastest of the tournament so far -- to seal a 2-1 lead.

They were neck and neck in the fourth too but Tiafoe was dialled in at the end when he was up 5-4, with Shelton having to save set points before an unforced error forced a decider.

Shelton was the first to crack in the fifth set when he tried too hard to go big with his shots and made errors as Tiafoe broke and then went 4-1 up.

Tiafoe did not look back and on his second match point he sneaked up to the net and finessed a volley into the open court, celebrating a first win over his compatriot before they embraced at the net.