The match lasted four hours and 49 minutes and did not conclude until 2:04 a.m. Wednesday morning.
Remarkably, Thiem was the first top-20 player Nadal has faced at Flushing Meadows since his final win over Novak Djokovic in 2013. ESPN captured that perfectly in a triumphant photo of the 32-year-old.
Next up for Serena is a quarterfinal meeting with eighth seeded Czech Karolina Pliskova who advanced with a 6-4, 6-4 win over 18th seed Ashleigh Barty of Australia. He also has wins over the Austrian at all three of the clay court Masters, including in the final in Madrid previous year. But the last time, against Philipp Kohlschreiber in Miami last spring, he fought back to win the match.
"Against Rafa, I've had three very nice experiences and seven frightful experiences", said Thiem who turned 25 on Monday. That was wrapped up in just 24 minutes with Nadal winning only seven points. "But in few days I will look back and will remember how great it was to play in front of a packed Arthur Ashe this great match".
But he took the tiebreaker before Nadal just proved the steadier of the two in the deciding and dramatic final set.
Perhaps Thiem, after a change of socks and shoes, looked the fresher going into the decider but he needed to save two break points at 2-2, one with an ace, to maintain parity.
The victory, which puts the defending champion through to his third consecutive Grand Slam semifinal, came hours after Williams booked her 12th U.S. Open semifinal and the night after Roger Federer was ousted by the unseeded Australian John Millman in the fourth round. "That's one more today", he said after his 0-6, 6-4, 7-5, 6-7 (4/7), 7-6 (7/5) win.
"Nobody´s game really matches up well with his", added Thiem who made his first US Open quarter-final with an impressive 7-5, 6-2, 7-6 (7/2) win over last year´s runner-up Kevin Anderson, the fifth-seeded South African.
"Yeah, of course, I played a lot of long and tough matches in my career". The fourth was a wild 81-minute ride that began with Thiem facing break points, saw the Austrian threaten a double break before being pegged back and then a tired Nadal miss a chance to win the match. "I mean, it's cruel sometimes tennis, you know, because I think this match didn't really deserve a loser". And I played against a great opponent.
This was tennis at its absolute best, according to David Law (BBC 5 Live) and Catherine Whitaker (Amazon Prime Video), and also a brilliant advert for fifth set tiebreaks.
And, as the tense match went on, the French professional tennis player seemed to get more emotional. "Not insane, but tough", Nadal said.
Despite that, the 29-year-old was never broken in the 3 hour 31 minute match where Isner unleashed 26 aces but was undone by 52 unforced errors compared to Del Potro's 14.
He revealed that he'd offered his condolences to ninth seed Thiem at the net, telling him that he was a good player and urging him to keep going.