Brazil’s highly rated teenager Joao Fonseca beat Miomir Kecmancovic to set up a second-round match against world number 21 Tomas Machac.
Fonseca beat the Serb 7-6 (7-3) 7-6 (7-5) 6-3 in two hours and 26 minutes.
The 19-year-old was forced to overcome illness in the third set, first calling the trainer for a medical timeout before rushing to the side of court to vomit into a bin.
“The first round is always a bit more tense and today I felt a bit more sick in the third set,” said Fonseca.
“I didn’t know what happened. I just threw up water. Sorry about that guys, I apologise!”
Elsewhere, world number 17 Frances Tiafoe beat Japan’s Yoshihito Nishioka 6-3 7-6 (8-6) 6-3.
American Tiafoe, who has been a semi-finalist at his home Grand Slam twice in the past three years, will face compatriot Martin Damm in the next round.
Denmark’s Holger Rune made heavy work of Dutchman Botic van de Zandschulp to record his first US Open win since 2022.
The 11th seed was two sets up with a 4-0 lead in the third set but lost the next four games to gift Van de Zandschulp a route back into the match.
But Rune held his nerve in the tie-break to seal a 6-3 7-6 (7-4) 7-6 (7-2) victory.
Ninth seed Karen Khachanov of Russia came from a set down to beat American Nishesh Basavareddy 6-7 (5-7) 6-3 7-5 6-1, while Russian 15th seed Andrey Rublev eased past Croatia’s Dino Prizmic 6-4 6-4 6-4.
Italian 24th seed Flavio Cobolli beat compatriot Francesco Passaro 7-5 4-6 6-4 3-6 6-3 in an epic lasting three hours 42 minutes.
In contrast, Norwegian 12th seed Casper Ruud dispatched Austrian Sebastian Ofner 6-1 6-2 7-6 (7-5) in under two hours.