The 14-time major champion has now failed to go past the fourth round in his last five grand slams, while Pouille advances to meet fellow Frenchman Gael Monfils in the quarter-finals.

Nadal led by 4-2 and a break in the deciding set in Arthur Ashe Stadium but Pouille broke back, winning four out of the next six games to force a tie-break.

The 22-year-old then pulled 6-3 clear to open up three match points but, while Nadal saved them all, he then missed a simple forehand and Pouille pounced to snatch a momentous victory.

"It took everything," Pouille said on court afterwards.

"It is my first match on the centre court against Rafa. I couldn't dream better than this.

"With three match points I thought, 'you are going to win this one'. At 6-6, I was not the same. Honestly I am the most happy in this tournament.

"It is never over until the last point. I was a break down in the fifth, I came back. It is never finished until the last point is over."

For Nadal, this is another crushing blow given the world number five arrived in New York buoyed after an impressive run at the Olympics.

A niggling wrist problem, however, had not completely healed in Rio and his elusive 15th major title, to add to the last he won at the 2014 French Open, appears ever further away.

The 30-year-old also fell victim to an inspired Pouille performance, the talented world number 25 unleashing a relentless display of power to record the biggest win of his career.

"I need something else," Nadal said. "I need something more that was not there today. I'm going to keep working to try to find.

"But, yes, it was a very, very close match where anything could happen. I just congratulate the opponent that probably he played with better decisions than me the last couple of points.

"Mental or physical doesn't matter. I am out of the tournament. Physical, for sure, no. I fight till the end. Of course it was not a physical thing.

"It was not a mental thing. It was sport and in sport you lose or you win. The opponent wants to win the same, like you."

Nadal has enjoyed greater success away from the grand slams this year but he rejected the suggestion he is struggling to cope with the pressure.

"After winning 14 and being in semi-finals a lot of times, you feel that's pressure?" Nadal said.

"I'm 30 years old. After having the career that I have, it is not a question of pressure."

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Pouille has now won three five-set matches in a row at the US Open after coming from behind to beat both Spain's Roberto Bautista Agut and Swiss qualifier Marco Chiudinelli.

The Frenchman also revealed how a recent practice session with Nadal helped him adjust his tactics ahead of the match.

"During the practice it was 6-1 6-3 for him. I was not confident before the match." Pouille said.

"He was playing very close to the baseline during the practice. If my return was not perfect, then he was going with the forehand and almost did only winners.

"So today I decided to be far from the baseline to hit the ball hard and try to then come closer. I think that was the good choice."

Novak Djokovic booked his place in the quarter-finals with a straight-sets win over Britain's Kyle Edmund. Djokovic will now face France's Jo-Wilfried Tsonga.