Alexei Popyrin entered the US Open in the best form of his career and with a tailwind of confidence after picking off a parade of higher-ranked players to win the Montreal Masters earlier this month. On Friday night, the 25-year-old Sydneysider’s charmed summer reached new heights with a seismic upset of Novak Djokovic that propelled him into the second week of a major tournament for the first time in 23 appearances.

Popyrin, the No 28 seed, ran out to a two-set lead before holding on to win 6-4, 6-4, 2-6, 6-4 before a stunned crowd inside Arthur Ashe Stadium, denying the second-seeded Djokovic in his bid for a record 25th grand slam singles title and a rare US Open repeat. He advances to the fourth round in a suddenly wide-open quarter where he will meet Frances Tiafoe, the 20th seed who came through a 4-6, 7-5, 6-7 (5), 6-4, 6-3 thriller against fellow American Ben Shelton during the daytime session.

“Just an awful match for me,” said Djokovic, whose 14 double faults on Friday were a career-high for a grand slam match. “Tournaments like this happen.”

For lengthy stretches on Friday the 37-year-old Djokovic, wearing a sleeve over his surgically repaired right knee, was a silhouette of the ruthless winning machine that has piled up 24 major singles titles, appearing sluggish, disengaged mentally and at times indifferent to his crumbling fortunes.

The 6ft 5in Popyrin took full advantage, pounding 50 winners and finally breaking through after losing a pair of tightly wound four-setters to Djokovic earlier this year. The shock result sends the four-time US Open champion to his earliest exit at Flushing Meadows since a third-round defeat 18 years ago to Lleyton Hewitt, who took in this match from Popyrin’s players’ box.

“Third time lucky I guess,” Popyrin said. “We had battles at the Australian Open and Wimbledon. I had chances in those matches but didn’t take them. This match was different. I was able to take my chances when I had them. I played some good tennis.”

The opening stages unfolded deliberately and on even terms for the first eight games with Popyrin staring down the first moments of crisis, saving five break points while serving at 2-3. But it unravelled in a hurry for Djokovic as his opponent rattled off the last eight points of the set in succession, breaking and holding at love to take the opener in 45 minutes.

Facing another triple break point serving at two-all in the second, Djokovic saved a pair of them before sending a forehand approach shot wide of the tramline. Popyrin appeared to tweak his foot and began noticeably limping with Djokovic serving at 3-5, but he recovered during the changeover and coolly served out the set, closing it out with a beautifully executed serve-and-volley winner into the open court.

Perhaps surprised by his position, Popyrin was broken in his opening service game of the third set, getting just one of six first serves in. With the simple raise of a fist, it seemed Djokovic was back to life. At the same time a glut of unforced errors began creeping into Popyrin’s game: he made nearly as many in the third (18) as the first two sets combined (19). By the fourth, Djokovic was moving far better than earlier in the match and a ninth career win from two sets down appeared in the cards.

But the Australian No 2 held his nerve, going ahead a double break, saving seven of eight break points and staying on course for a career-best win. When Djokovic sent a forehand sailing past the baseline on match point after 3hr 19min, Popyrin stood behind the baseline with his arms elevated in triumph.

Popyrin’s season caught fire earlier this month in Montreal, where he buzzed to the most prestigious title of his seven-year career while knocking off five opponents ranked in the ATP’s top 20. The son of Russian immigrants is one of four Australian men in the third round at Flushing Meadows for the first time since 1997, along with Alex de Minaur, Chris O’Connell and Jordan Thompson, each hailing from the NSW capital.

Djokovic landed in New York for his first event since winning the Olympic title looking to go clear of Margaret Court’s all-time mark of 24 major championships, but he was also out to become the first back-to-back US Open men’s champion since Roger Federer won the last of five straight titles in 2008.

But Popyrin ensured this season will mark the first in 22 years that none of Djokovic, Roger Federer or Rafael Nadal will have won one of the sport’s four bedrock tournaments.

“I spent a lot of energy winning the gold, and I did arrive to New York just not feeling fresh mentally and physically,” Djokovic said. “But because it’s US Open, I gave it a shot and I tried my best. I didn’t have any physical issues. I just felt out of gas and you could see that with the way I played.

“Just from the very beginning, from the first match, I just didn’t find myself at all on this court. It’s all I can say. Life moves on. [I’ll] just try and recalibrate and look for what’s next.”