It's a Grand Slam heartbreak yet again for Rafael Nadal.

Lucas Pouille outlasted 14-time Grand Slam champion Nadal in a five-set classic on Sunday to lead a trio of French men into the quarter-finals of the US Open.

Pouille, 22 and ranked 25th in the world, lived up to the promise of his quarter-final run at Wimbledon, emerging from a roller-coaster ride with a 6-1, 2-6, 6-4, 3-6, 7-6 (8/6) triumph over the Spanish superstar.

The defeat leaves Nadal -- forced out of the French Open third round with a wrist injury that also saw him miss Wimbledon -- without at least one Grand Slam quarter-final appearance for the first time since he was a teenaged tour newcomer in 2004.

Pouille came out firing, pushing Nadal back with an array of deep groundstrokes and angled shots.

Fifty-two winners from Nadal -- whose attacking response saw him come out a winner on 35 of 48 forays to the net -- weren't enough.

The taut battle came down to the fifth-set tiebreaker and Nadal, trailing 3-6, showed his mettle by saving three match points -- the third on Pouille's serve.

Then he smacked a forehand into the net to give Pouille one more chance and the French player pounced on it with a blazing forehand that kissed the sideline.

"I wanted to take my chance to be very aggressive, try to play with my forehand, and so that's what I did at the (last) match point," Pouille said.

Nadal acknowledged that his sloppy forehand was "a big mistake".

"But you are six-all in the tiebreak. I played the right point. I put myself in a position to have the winner and I had the mistake. That's it. You cannot go crazy thinking about these kind of things.

"The problem is arriving at six-all in the fifth, I should be winning before," said Nadal, who opened the fifth set with a break but couldn't hold onto it, dropping his own serve in the eighth to make it 4-4 and set the stage for the tiebreaker.

"I fought until the end," Nadal said. "There's things I could do better, but I had the right attitude. I needed something more -- it was not there today."

The four-hour, seven-minute contest entranced the crowd in Arthur Ashe stadium, where Pouille recalled admiring Nadal as a youngster.

Pouille, who has now won three successive five-setters to reach the last eight, wasn't intimidated by the massive Ashe stage, even though he only practiced on it last year.

"I think it was the best atmosphere I played on a center court," he said of the 22,000-seat cathedral of tennis.

"At the end it was full. Sometimes I couldn't even hear myself when I was saying 'Allez, allez, allez.'"

Another Frenchman Jo Wilfred Tsonga next faces world number one and defending champion Novak Djokovic, who powered past 84th-ranked Kyle Edmund of Britain 6-2, 6-1, 6-4.

"Feels great to play a full match after a weird couple of days when I didn't have too much tennis," said Djokovic, who was handed a walkover into the third round by injured Czech Jiri Vesely and played just six games before third round opponent Mikhail Youzhny retired hurt.

The remaining round of 16 matches were scheduled for Monday, when world number two Andy Murray will take on Bulgarian Grigor Dimitrov.

Third-seeded Stan Wawrinka, sixth-seeded Kei Nishikori of Japan, eighth-seeded Austrian Dominic Thiem and former champion Juan Martin del Potro will also battle for quarter-final berths.