Briton’s Kyle Edmund lost to US Open top seed Novak Djokovic, while compatriot Cameron Norrie advanced to the third round of a Grand Slam for the first time.
Edmund, 25, unexpectedly won the first set but ultimately struggled to keep up with the world number one’s intensity.
The 33-year-old maintained the level that has helped him stay unbeaten in 2020 and won 6-7 (5-7) 6-3 6-4 6-2.
Norrie, 25, beat Argentine Federico Coria 6-3 6-4 6-4.
The world number 76 upset ninth seed Diego Schwartzman in the first round and will face Spanish world number 99 Alejandro Davidovich Fokina next.
Djokovic is seeking his 18th Grand Slam title and plays German 28th seed Jan-Lennard Struff in the third round.
Edmund unfazed in first set
Djokovic has looked imperious all year, winning January’s Australian Open, February’s Dubai Tennis Championships, and, more recently, the Western & Southern Open on Saturday.
But British number two Edmund looked unfazed and used his characteristically powerful forehand on Arthur Ashe Stadium.
Djokovic repeatedly turned to drop-shots, but the tactic was fruitless as the Briton saw them coming every time in a high-quality first set.
A 100mph forehand winner and an ace down the middle were two highlights for the world number 44 en route to winning the set with compatriots Andy Murray and Dan Evans watching from the stands.
Meanwhile Top seed Karolina Pliskova was knocked out of the US Open in the second round with a heavy defeat by France’s Caroline Garcia.
Pliskova, runner-up in 2016, lost 6-1 7-6 (7-2) to the world number 50.
Czech world number three Pliskova was the highest ranked player here in the absence of Australian Ashleigh Barty and Romania’s Simona Halep.
Meanwhile, other seeds to tumble were Elena Rybakina (11), Marketa Vondrousova (12) and Alison Riske (13).
But there were victories for fourth seed Naomi Osaka, sixth seed Petra Kvitova, eighth seed Petra Martic and Estonian 14th seed Anett Kontaveit.
‘I am not a robot’ – Pliskova
Six of the world’s top 10 players were already absent from the behind-closed-doors tournament amid the coronavirus pandemic.
And Pliskova’s exit may further improve Serena Williams’ chances of a record-equalling 24th Grand Slam singles title in an open women’s draw.
Pliskova hit just one winner in a poor first-set performance and fell a break down early in the second – smashing a racquet in frustration – before improving her level to carve out two set points.
But she failed to convert them and Garcia went on to take it to a tie-break, which she dominated.
“I thought she played great tennis in the first set,” Pliskova said. “She was just playing super aggressive, going for her shots.
“I maybe didn’t play my best. But that’s how it is sometimes. I’m not a robot, so I don’t have to play every day amazing.”
Garcia, who has won seven tour titles, will face American world number 41 Jennifer Brady in the next round.