This was Pouille's third career victory in a five-setter; all have come in his past three matches.
Since losing in last year's French Open quarterfinals, Nadal has failed to make it beyond the fourth round at a major.
In 2016, he lost in the first round of the Australian Open. Then he pulled out of the French Open before his third-round match because of a torn tendon sheath in his left wrist, an injury that forced him to withdraw from Wimbledon altogether and miss about 2 1/2 months on tour in all.
He led by a break at 1-0 and 4-2 in the fifth set, but Pouille broke back to 4-all, and eventually converted his fourth match point in the tiebreaker with a gutsy forehand victor to close a 16-stroke exchange.
Some hesitant tennis saw her hand the break back, though once again it didn't matter as the Brit hit a forehand error, as well as two drop shots which the Latvian easily go to, to set up three break points; she only needed one, hitting a flawless drop shot victor. "Mentally I'm spent, totally spent".
These two have played once in the past, which was in the 2011 Australian Open, a match Wozniacki won in straight sets.
The win means that Sevastova continues her Cinderella run, which is occurring just a year since a return to tennis after retiring aged just 23 back in 2013.
She won her first WTA title in Stanford, she reached the Olympic quarter-final, and she defended her points from previous year to help consolidate her rise to just outside the Top 10.
"I'm playing better in my second career right now", she said.
The 25-year-old is quoted by The Mirror as saying: "I felt I did the best I could today".
If Konta seemed to be fighting a physical battle, then Sevastova's challenges were largely mental.
As in her second-round upset of third-seeded Garbine Muguruza, Sevastova wobbled under the pressure at first, failing to serve out the match. And as in that victory over the French Open champ, she finally closed out the win with a service break.
No sooner had the Briton found her groove, however, than she lost it again, playing a terrible service game to be broken again as Sevastova clinched the set.
Three years ago Sevastova gave up tennis, fed up with injuries and poor form, and her only time spent with a racket came when giving lessons down at her local club.
Konta stopped short of admitting it in her postmatch press conference, but her second-round health scare - when she dramatically collapsed in the 80 percent humidity at Flushing Meadows - may have caught up with her as she ran out of steam. "But even though I had match point, I knew that with the sun at one end and the shade at the other I'd get another chance to break her".
MEN'S RESULTS (Fourth Round): No. 24 Lucas Pouille outlasted two-time U.S. Open champion Rafael Nadal in five sets, No. 9 Jo-Wilfried Tsonga defeated No. 26 Jack Sock in four sets and No. 10 Gael Monfils beat Marcos Baghdatis in straight sets.
The British No. 1 made a awful start with Sevastova, now the first Latvian woman to make the quarterfinals of a Grand Slam since Larisa Savchenko in 1994, one point away from a 4-0 lead in the first set.