The defending champion was a break down at 5-4 but fought back to move two sets to one up and, though he was unable to close the match out in the fourth, he did so in the fifth-set tie-break, setting up an enticing encounter with Juan Martin del Potro in the semi-finals.
Rafael Nadal was forced to go the distance in an epic five-setter against Dominic Thiem in their US Open quarter-final, while Serena Williams fought back to beat Karolina Pliskova and reach the semi-finals in NY.
After suffering a first set "bagel", Nadal had to battle back from breaks in the third and fourth sets before seeing off the first top 20 player he had faced at the US Open since 2013. "It was a real battle".
"Whatever the humidity is on outer courts or in the city, I think it's amplified on centre court", Isner said. For me it was...
"Yeah, it's going to be stuck in my mind forever", Thiem said after the match. Nadal failed to serve out the set at 5-3, then promptly broke Thiem's serve for the second straight time to even the match.
"Tennis is sometimes cruel, this game didn't deserve a loser but there has to be one and, if we skip the first set, we were well matched from start to finish", he noted.
"I'm very sorry for Dominic", Nadal added.
After winning the fourth in a tiebreaker, this time drawing an error from Nadal at the net, Thiem found his bearings in the forecourt in the final set, winning seven of his first eight forays forward.
Thiem took the first set in just 24 minutes, stunning a packed crowd at Billie Jean King National Tennis Center.
It's Theim's best ever performance at a US Open, but commentator John McEnroe says the Austrian will need to dig deep to come back from this defeat.
His victory against the world number one in the Madrid semi-finals ended Nadal´s 50-set clay win streak which began after the Austrian had beaten him in Rome 12 months earlier.
Williams, the 23-time Grand Slam champion seeking a first major since a 2017 Australian Open title won when she was pregnant with her daughter Olympia, will take on Karolina Pliskova for a semi-final spot after the eighth-seeded Czech beat Australian Ashleigh Barty 6-4, 6-4. I fought until the end. I was struggling also a little bit, but I didn't show it that much.
"It wasn't easy, obviously, I think one thing she did well was change her strategy and started doing just a completely different game and gave me a different look to her game", explained Serena, who laid down 18 aces. "But I just keep going".
With his first words to the media, Thiem underscored the weight of this match to both men.
Nadal won just seven points for the entire set, his nine unforced errors handing the set to Thiem on a plate. I told him I was sorry and that he is good, he is a fighter.
When the ninth-seeded Thiem forced deuce in that game, Nadal rewarded his friend with a small clap from the other end of the court. "But I don't play dropshots when I see the player struggling or bending over, no", Sevastova said. And I played against a great opponent.