He picked himself up and dusted himself down to play on for another eight games, but it was a different story an hour later when there was nothing left to fight for.
"Obviously I saw Rafa before his first round match and the way he practised and how flat he was hitting after just a few days following on from the French Open, it's incredible how quickly he can turn it around".
"After nearly five hours match, I fell down".
"I'm trying to get to where he's already been", said Isner, who has won all 95 of his service games this fortnight, thanks in part to a tournament-leading 161 aces. Djokovic has the slight edge at overall Tour-level at 26-25, but Nadal ended a seven-match losing streak against the Serb at Madrid previous year and also won their only meeting so far in 2018 in the semi-finals of the Rome Masters.
The world number one then wasted four set points in the second.
One of those was on double fault in the tiebreak and the giant Argentine pounced to level the tie.
Nadal carved out the crucial break in the opening set for a 6-5 lead and claimed the opener off a Del Potro backhand error.
"I think it was great quality tennis and in the final set there were some unbelievable points", said 2008 and 2010 champion Nadal.
A tired Del Potro, a semi-finalist in 2013, finished with 33 aces and 77 winners but even those impressive statistics were not enough.
"I wanted to stay there", del Potro said afterward, "all night long". I knew I was in a good spot. "But maybe tomorrow or after tomorrow when I get home and I watch the match or some points again, I will be glad with my level, with my style of game".
World number one Nadal, the 2008 and 2010 champion at the All England Club, trails Djokovic, the 2011, 2014 and 2015 victor, 26-25 in a rivalry which began at Roland Garros 12 years ago.
With the increasingly physical nature of rallies, the advances in training and nutrition that help extend careers, and the dominance of a certain trio of all-time talents _ Federer has 20 Grand Slam titles, Nadal 17, Djokovic 12 _ it's been hard for any youngsters to elbow their way to the top. "In some ways he deserves to win as well", said Nadal after the breath-taking quarter-final.
"The last set had a little bit of everything, great points, great rallies, he was hitting insane with his forehands".
A couple of slips from the fifth seed gave Nadal a sniff and after the Spaniard broke for a 3-2 lead in the fourth, Del Potro thumped a ball at full pelt into the turf in frustration.
Meanwhile, Djokovic, a 12-time Major victor has warned Nadal that he is playing his best tennis this year.