Kristina Mladenovic upset former world number one Angelique Kerber 7-5 0-6 6-4 on Monday.
The win put an early end to the 2016 U.S. Open champion’s bid for a second trophy at Flushing Meadows.
Mladenovic suffered back spasms which twice required medical attention in a second set dominated by the German.
But she recovered in the decider, breaking Kerber in the first game to seize the momentum.
Kerber battled back to tie the set at 3-3 but the Frenchwoman broke the 14th seed again to take a 5-4 lead.
She crushed her 46th winner, a forehand from the baseline, on match point to end the nearly two-and-a-half-hour encounter.
The outcome registered as a surprise but not quite a shock.
Kerber, in recent months, has not looked like the player who won both the U.S. and the Australian Opens in 2016 before capturing the Wimbledon championship last year.
“It was not my best match but she played a good tactic against me,” Kerber told reporters.
“I played good in the second set and (it) was (an) up-and-down match,” she said.
“The first rounds are always not so easy, especially since I played not so well in the last few weeks.”
Kerber has particularly struggled at Grand Slam events this year.
She fell in the fourth round of the Australian Open, the first round of the French Open and the second round of Wimbledon prior to Monday’s first round exit.
“Every Grand Slam is a new tournament. And, yeah, this year it was not really the best year for Grand Slams for me,” she said.
In spite of the disappointing results, Kerber said she had no plans to reunite with coach Torben Beltz, after they parted company in 2017 following her sensational 2016.
“No, I think Torben has a good job right now,” she said of the German coach, who now works with Donna Vekic.
“And we are still friends and I think it’s good like it is now,” she added with a smile.