Eleventh seed Danielle Collins, making her final Grand Slam singles appearance, was beaten 1-6 7-5 6-4 by fellow American Caroline Dolehide.
Collins, runner-up at the Australian Open in 2022, went on a stunning run earlier this season but was unable to find that form at her home Grand Slam.
The 30-year-old will have another shot at a trophy in the women’s doubles alongside Caroline Garcia and said she had requested not to have any on-court presentation after her final match at Flushing Meadows.
“I’ve struggled with feeling guilt around success, and that’s something I have had to work on,” Collins explained.
“I’m not great, honestly, at having an all-about-me moment. I would prefer to do something like that maybe in private.
“I feel like I’ve gotten enough attention to last a lifetime.”
Elsewhere, former Wimbledon champion and fourth seed Elena Rybakina claimed a straightforward 6-1 7-6 (7-1) victory over Australian qualifier Destanee Aiava.
Former French Open finalist Karolina Muchova advanced with a 6-3 7-5 win over home hope Katie Volynets, while former world number one Caroline Wozniacki thrashed Japan’s Nao Hibino 6-0 6-1 in just 53 minutes.
Russian teenager Mirra Andreeva also made light work of her opening match, beating Camila Osorio 6-2 7-6 (7-4).
There were upsets, however, for 2021 runner-up Leylah Fernandez, who lost 2-6 6-4 7-5 to Anastasia Potapova, and French 28th seed Caroline Garcia, beaten 6-1 6-4 by world number 92 Renata Zarazua of Mexico.
