Rafael Nadal struggled mightily before falling 6-1, 2-6, 6-4, 3-6, 7-6 (8-6) to Lucas Pouille at the US Open on Sunday in a fourth-round marathon that lasted more than four hours.
The two-time champion was unable to capitalize on a 1-0 lead in the fifth set against the record third Frenchman to reach the last eight in New York - a first in the Open tennis era.
Novak Djokovic played his first match since the first round after a pair of walkovers, hammering Brit Kyle Edmund 6-1, 6-2, 6-4 in a post midnight finish
"It was great to play a match," the current title holder said. "I'm glad to be back after a weird week. I came out of the blocks well and started with the right intensity."
"I made him work for each point."
The top seed had a brief stumble in the third set before coming back from a break and taking the victory.
Nadal, 30, saved three match points in the decider but stuffed a forehand volley into the net to yield a fourth winning chance for his 22-year-old opponent.
"There were things I could do better, but I had the right attitude," Nadal said. "I fought right up to the last ball.
"But something more was not there today. I'm going to keep working to try to find it. I congratulate my opponent who probably played with better decisions than me on the last couple of points."
Pouille earned the biggest win of his career, wrapping it up with a forehand down the line.
"I couldn't dream better than this," he said.
Nadal has lost his last three five-set matches at the majors. The fourth seeded Spaniard came to the court having dropped only 20 games and stood perfect on sets before facing Pouille, a Wimbledon quarter-finalist.
Pouille now plays compatriot and tenth seed Gael Monfils, who beat Marcos Baghdatis 6-3, 6-2, 6-3.
The Cypriot is likely to be sanctioned after being caught scrolling through a phone during a changeover, a major disciplinary breach due to anti-corruption protocols.
Monfils kept his trick-shots to a minimum as he played it strictly business against Baghdatis.
"He's a good friend. I've known him for a long time," Monfils said. "I had [to]serve very consistently because he's a pretty good returner."
"I guess everything was fine today," the two-time New York semi-finalist said.
Ninth seed Jo-Wilfried Tsonga booked his spot as he knocked out the final American man in the tournament, Jack Sock, 6-3, 6-3 6-7 (7-9), 6-2.
The French player is into the New York last eight for a second straight edition.
Second seed Angelique Kerber beat Petra Kvitova 6-3, 7-5 to put more pressure on Serena Willimas.
The American now has to reach the Saturday final in order to prevent her German rival from seizing the top ranking for the first time.
Kerber counts the event as the starting point of her career after she reached a semi-final in 2011.
Kerber will next face Roberta Vinci, the 2015 women's finalist, who returned to the quarters by defeating Lesia Tsurenko, 7-6 (7-5), 6-2.
Last year Vinci knocked Serena Williams out in the semi-finals, then lost an all-Italian final with Flavia Pennetta.
Former number one Caroline Wozniacki, twice a finalist, continued to surge after injury frustration as she eliminated US eighth seed Madison Keys 6-3, 6-4.
The number 74 will next play Anastasija Sevastova, who exited the tour with injury and motivation worries for 18 months from 2013-15. The Latvian beat British 13th seed Johanna Konta 6-4, 7-5.