Fils, who had taken the first set 6-4, served for the second set against the 28-year-old Greek at 5-3 up.
But he fluffed the opportunity. Tsitsipas then held serve to level at 5-5 before winning the set on a tiebreak.
Tsitsipas, a formerworld number three, surged away to take the match in four sets.
"I don't really know what happened," said Fils who entered the US Open as 10th seed and one of the favourites for the title following his run to the quarter-finals at the Montreal Masters 1000 and his title at the Cincinnati Masters 1000.
"I don't have the answer," added the 22-year-old. "But the energy went down at the end of the second set and I never felt again a good energy.
"At my level, to make such a mistake is almost unprofessional."
Fils heads into US Open as leader of the French pack as Djokovic bows out
Disappointment in New York
Fils rose to a career-high of 11 in the world on the back of his success at the Cincinnati Masters which is one of the most coveted titles on the international circuit after the four Grand Slam tournaments in Melbourne, Paris, London and New York.
"Of course, I'm pretty happy with the way I played in Montreal and Cincinnati but very, very, very disappointed with the way I played in New York.
"So now I see more dark than pink, but it's okay."
Fils was the most notable defeat among the French first-round casualties in the men's draw.
French Open draw sees Boisson face Kalinskaya and Sinner take on Tabur
French losses in New York
Fils's good friend, Giovanni Mpetshi Perricard, lost to Jurij Rodionov from Austria in straight sets while Hugo Gaston was dispatched by the 2021 champion Daniil Medvedev and Térence Atmane went down to Jaume Munar.
Of the 13 Frenchmen who started the final Grand Slam tournament of the 2026 season, four have reached the second round while five – including Gael Monfils – are due to begin their campaigns on Tuesday.
In the women's draw on Tuesday, Léolia Jeanjean will take on the Dutch qualifier Arantxa Rus, aiming to join France's top female player Diane Parry in the second round.
Parry, who claimed her first WTA title last Saturday in Monterrey, Mexico, beat Viktorija Golubic from Switzerland 7-5, 6-4 to reach the second round for the third consecutive year.
On Monday, Emma Navarro from the United States beat Lois Boisson and Marie Bouzkova from the Czech Republic saw off Elsa Jacquemot 6-2, 6-2.



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