On a rainy night in New York, Osaka was beaten by American Danielle Collins in straight sets — 7-6(5) 6-3 — while defending champion Emma Raducanu fell to Alizé Cornet.
Raducanu, 19, stunned the world by winning her maiden grand slam at Flushing Meadows last year, but has struggled to find similar form since.
The experience and intensity of the experienced Cornet proved too much for her as she was beaten in straight sets – 6-3 6-3.
“This one obviously hurts a bit because it’s my favorite tournament and there’s been a lot of emotion over the past year,” she told reporters after the loss.
“I’m proud to have given myself every game, every day, knowing that I push myself to be the best I can be.”
Raducanu will fall in the rankings after a frustrating year which has been marred by injuries and changes in his coaching staff.
The youngster struggled to come to terms with life on the full WTA Tour but showed flashes of quality that won her her first Grand Slam title just 12 months ago.
Cornet was simply in better shape and is no stranger to big Grand Slam results, having already beaten Iga Swiatek at Wimbledon.
The Frenchwoman now holds the Open era record for the most consecutive Grand Slam appearances, having appeared in the previous 63.
“I think I manage my emotions better,” Cornet told reporters after the game. “I guess I’m getting older – more mature. It shows in my results. I’m 32 – better late than never.”
“She definitely booed me last time”
Osaka suffered a similar experience to Raducanu but this time at the hands of the talented Collins.
The world No. 19 had never even won a set against Osaka in their previous three encounters, but this time around he overtook the four-time Grand Slam champion.
“When you lose to someone three times, you get a lot of insight into what you can do better,” Collins told reporters.
“With Naomi being the player she is, she definitely booed me last time out. I just had to learn from that and make adjustments and I think I did.”
Two-time US Open champion Osaka has not been ranked this year and is currently ranked 44th in the world.
Struggling with momentum and form, she was likely a first-round underdog but gave an impressive performance despite the loss.
Collins will now face Spanish qualifier Cristina Bucșa in the next round while Cornet will face Katerina Siniaková.