Third seed Felix Auger-Aliassime tumbled out of the US Open on Thursday as former champions Iga Swiatek, Naomi Osaka and Coco Gauff reached the third round.
Karen Khachanov, ranked 50th in the world, downed Auger-Aliassime 6-7 (5/7), 6-3, 6-2, 6-2, pulling away relentlessly from the physically ailing Canadian who said he was "dizzy and seeing spots.
"I thought maybe it would pass, but it didn't," a dejected Auger-Aliassime said.
Khachanov took full advantage of 47 unforced errors, with eight double faults, from Auger-Aliassime, who struggled particularly on serve.
"I thought maybe he had some physical issues, it's part of our sport," Khachanov said. "From my side I tried to give my best performance, fighting, fighting.
"I'm super happy to get this win," added the 2022 semifinalist after posting his first top-10 win of the year.
It was the second big upset on the men's side, after Novak Djokovic was ousted in the first round.
Sixth-seeded Australian Alex de Minaur also bowed out, falling to Botic van de Zandschulp 6-4, 7-5, 6-2 to further open up a men's field headed by world No 2 Alexander Zverev.
French Open champion Zverev anchored the night session on Arthur Ashe Stadium, taking on 52nd-ranked Frenchman Quentin Halys.
Meanwhile three former women's champions – Swiatek, Gauff and Osaka, booked their third-round berths.
Gauff thrilled the Ashe night crowd with a 6-4, 7-6 (7/5) victory over former world No 2 Paula Badosa of Spain.
Swiatek marched through with a 6-3, 6-2 victory over Nadia Podoroska while Osaka survived a second-set swoon to beat Katerina Siniakova 6-2, 5-7, 6-1.
Gauff, 22, had lost five of her eight prior meetings with Badosa, so she was ready when the Spaniard piled on the pressure in the second set, regaining a break to force the tiebreaker.
"I knew she would raise her level. She's capable of blasting winners and blasting return winners," said Gauff, who was pleased she kept her composure.
"I think I need matches like this to build my confidence," the 2023 US Open winner said.
Swiatek, whose six Grand Slam titles include the 2022 US Open, had things mostly her own way against Podroska, a former top-40 player now sunk to 449th in the world.
She fought off four break points at 5-3 in the first set then pulled away to polish off the win in little more than an hour.
It was another encouraging performance for the former world No 1, who hadn't reached a final in 2026 until her run to the title at Toronto in August.
OSAKA FIGHTS
Japan's Osaka, who counts two US Open titles among her four major trophies, looked in total control against Siniakova as she raced through the first set and to a 4-2 lead in the second without facing a break point.
But the Japanese star's unforced errors began to pile up and doubles world No 1 Siniakova pounced to climb from 5-3 down and take the set.
Osaka regrouped in the decider, riding a quick break to a 3-0 lead and fending off a pair of break points on the way to victory.
"I just felt like I had to fight," she said.
So did former Australian Open champion Madison Keys, who saved five match points as she rallied from 5-2 down in the third set to beat Anna Bondar 4-7, 6-4, 7-6 (10/5).
In other early matches, reigning French Open champion Mirra Andreeva, seeded fifth, rolled over Germany's Eva Lys 6-0, 6-2.
Australian Open champion Elena Rybakina was in action later, taking on Spain's Jessica Bouzas.
Generations collided on Louis Armstrong Stadium, where 20-year-old American Learner Tien ended 40-year-old Gael Monfils's Grand Slam career with a 6-3, 6-4, 6-3 victory.
Monfils felt the love in New York, where he made his US Open debut in 2005, chants of "Monfils" erupting frequently and intensifying in the third set.
"It's been a long ride," Monfils said. "You are my second best crowd. Of course, it can't top Paris, but you are up there!"