Ivanovic has never been beyond the fourth round at the US Open
World number one Ana Ivanovic was sent crashing out of the US Open by French qualifier Julie Coin, who claimed a shock 6-3 4-6 6-3 second-round win.
Coin, ranked 187 places lower than the Serbian, won four successive games to take the first set from 2-3 down.
Ivanovic hit back to take the second set thanks to a vital break at 4-4 but made a string of unforced errors as Coin ran away with the decider.
Coin, 25, will play former world number one Amelie Mauresmo in the third round.
"Today I felt nervous at the beginning and then it went away," said Coin. "I don't know how I did it.
"I am not thinking about anything right now. Just enjoying the moment."
Ivanovic's exit was the earliest by a top seed at the US Open since the start of the professional era in 1968.
All I have to do is put some hard yards on the court and go back out there and work hard
"This is very disappointing to me but something I have to accept," she said. "I never saw her play before so I didn't know what to expect.
"She played a lot better than I expected. She served very well."
The 20-year-old Serb had scraped through her first-round match against Russia's Vera Dusevina but paid the price for another nervy display.
Ivanovic's form completely deserted her at times, with her forehand particularly fragile, but a lack of mental fortitude was the main reason for her defeat.
While the unheralded Coin, who is in the main draw of a Grand Slam tournament for the first time, grew in confidence as the match went on, Ivanovic crumbled.
At 2-2 in the third set, Ivanovic led 0-40 on the Coin serve but three wayward shots allowed the Frenchwoman to hold and she broke to love in the next game before serving out for victory.
Ivanovic refused to blame the thumb injury that ruled her out of the Olympic Games earlier this month.
"Today I didn't feel it," she said. "I'm just happy to be back on track without pain.
"Now all I have to do is put some hard yards on the court and go back out there and work hard."
Next up for Coin is Mauresmo, the 32nd seed, who beat Estonia's Kaia Kanepi 2-6 6-4 6-0.
"It will be like playing a number one because she used to be number one," Coin said of Mauresmo.
Elsewhere, seventh seed Venus Williams and fourth seed Serena Williams both made quick progress.
Venus - a two-time champion at Flushing Meadows - beat Paraguay's world number 113, Rossana De Los Rios, 6-0 6-3.
The reigning Wimbledon champion, who collected titles here in 2000 and 2001, only wobbled came when she squandered four match points on serve before completing her win at the fifth attempt.
"I think I just had a lot more power than she did," said Venus, who is scheduled to meet her sister in the quarter-finals.
Serena thrashed Russia's Elena Vesnina 6-1 6-1 in the first of the night matches on Arthur Ashe Stadium.
Venus will meet Alona Bondarenko of the Ukraine in round three after the 27th seed beat Sabine Lisicki of Germany 6-4 1-6 6-4.
Sixth seed Dinara Safina had to work hard to beat Italy's Roberta Vinci 6-4 6-3 to seal her progress.
Safina has won 17 of her last 18 matches but struggled for consistency against the world number 164 before eventually wearing her down.
"I think it still could be better, especially I was 4-1 up in the first set and then I let it go to 4-4," she said.
"I think there is much more room that I can play better."
Safina will play Timea Bacsinszky in the third round after the Swiss beat Chan Yung-jan of Taiwan 6-3 6-2.
There were also wins for Polish ninth seed Agnieszka Radwanska, Flavia Pennetta, the 16th seed from Italy, and France's Alize Cornet, the 17th seed.
But 13th seed Agnes Szavay and 20th seed Nicole Vaidisova are both out.
Hungarian Szavay lost 5-7 6-2 6-3 to Italy's Tathiana Garbin while Vaidisova, of the Czech Republic, tumbled to a 7-5 6-3 defeat against France's Severine Bremond.