Grand Slam finalists Stefanos Tsitsipas and Casper Ruud became two of the highest US Open men's seeds to fall in shock second-round defeats.
Seventh seed Tsitsipas lost 7-5 6-7 (2-7) 6-7 (5-7) 7-6 (8-6) 6-3 to Swiss qualifier Dominic Stricker.
Ruud, seeded fifth and last year's runner-up, lost 6-4 5-7 6-2 0-6 6-2 to Chinese world number 67 Zhang Zhizhen.
But second seed Novak Djokovic cruised through with a 6-4 6-1 6-1 win over Spain's Bernabe Zapata Miralles.
Djokovic, who is aiming to match Margaret Court with a record-equalling 24th major title, was already the heavy favourite to reach the men's final from the bottom half of the draw.
Now his pathway has been made even smoother - on paper, at least - by the exits of Tsitsipas and Ruud, who joined Danish fourth seed Holger Rune as an early casualty in this section.
Serbia's Djokovic plays compatriot Laslo Djere on Friday for a place in the last 16.
"I still feel like I can play better but I'm happy to be back playing in New York," said Djokovic, who has won three titles at Flushing Meadows.
"That's what gives me strength at 36 years of age. I still have the hunger and the desire to play my best tennis on this court.
"Every single match I play myself the most, in my mind. If I win this battle, then I win the battle outside against the opponent."
American ninth seed Taylor Fritz is still a prospective quarter-final opponent for Djokovic after he cruised past Peru's Juan Pablo Varillas in a 6-1 6-2 6-2 success.
Fritz was one of four American players to go through on Wednesday as the host nation looks for a first home men's champion since Andy Roddick in 2003.
Tenth seed Frances Tiafoe also won in straight sets against Austria's Sebastian Ofner, but 14th seed Tommy Paul had to fight back from two sets down to beat Russia's Roman Safiullin.
Big-serving youngster Ben Shelton edged a tight first set against 2020 champion Dominic Thiem before the Austrian, fighting his way back up the rankings after spending 10 months out last year with a wrist injury, retired early in the second set through illness.
Stricker is making his US Open debut but the 21-year-old has displayed a calmness and self-belief that belies his age so far at this tournament.
Both of those qualities were evident at a crucial point of the fifth set against Tsitsipas.
Leading 5-2 up and a game away from the biggest win of his career, he was singing along to Whitney Houston's I Want to Dance With Somebody as it played out around the court.
"I felt pretty good from the first set onwards," said former junior French Open champion Stricker, who saved a match point before winning his second qualifying match.
"It was a tough battle but I'm just super happy right now.
"Right now the belief is very, very high. The confidence is high and I believe a lot in myself."
But it was another early exit for Tsitsipas, who has never gone past the third round in New York.
The Greek, who reached this year's Australian Open final and the 2021 French Open final, served for the match at 5-3 in the fourth set but could not close out and paid the price.
"Usually, I'm much tougher mentally and I have shown it by coming back," said the 25-year-old, who has replaced his father Apostolos as his main coach with former Wimbledon finalist Mark Philippoussis.
"Even though sometimes I get broken serving for the match, let's say, I still find ways in the tie-breaker or perhaps in the fifth set if that has ever happened.
"Today was not the case. I was not able to bounce back after it."
Stricker will face wildcard Benjamin Bonzi in the third round after the Frenchman beat American Christopher Eubanks, seeded 28th, 7-6 (8-6) 2-6 6-2 7-6 (9-7) on court 17.
Wimbledon quarter-finalist Eubanks ran off the court with the scores level at 5-5 in the fourth set having earlier asked the umpire if he could concede the game to have a bathroom break.
With Bonzi 40-0 up, Eubanks dashed to the dressing room, allowing the Frenchman to hit an unopposed winner.
The 27-year-old returned and, down 5-6 in the fourth, held serve to force a tie-break which he lost 9-7.
The American, who was beaten in five sets by Daniil Medvedev in the last eight at this year's Wimbledon, has yet to advance beyond the second round at his home major.
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