Nadal had not lost a set prior to his first quarterfinal at the All England Club since 2011, but was taken the distance in an epic encounter between two warriors of the game.
It also followed a semi-final defeat to Nadal at the French Open last month where he won just seven games.
"Rafa is a fighter", del Potro said. The final set there were some incredible points. The hard-serving American beat Milos Raonic of Canada 6-7 (5), 7-6 (7), 6-4, 6-3 to set up a meeting with Federer's conqueror Kevin Anderson in the last four.
A tired Del Potro, a semi-finalist in 2013, finished with 33 aces and 77 winners but even those impressive statistics were not enough.
Nadal worked the angles and moved superbly from the start, but the heavy-hitting Del Potro frustrated him by saving the first two break-point opportunities of the match before holding to level at 4-4.
For all that Nadal plays tennis as if he had just disturbed a burglar making off with his 17 grand slam trophies, he prefers victory by stealth, sapping opponents of the will to chase.
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"I do think that towards the end of the match there was a certain dampness in the sections where there was still grass, nearer the net, when the humidity drops", Nadal explained in his Spanish language press conference.
Nadal saved three break points before an imperious forehand victor put him 5-3 up and he put away a simple volley to finally finish off Del Potro, then made his way around the net to embrace his tired opponent as he lay on the court following another tumble. "In some ways he deserves to go through too". But he blew those three set points, the last with a double-fault he later called "a big mistake". I tried to resist and maintain focus.
In the next game, Nadal staved off two break points, the first when he used his never-give-up-on-a-ball defense to stretch a point and del Potro pushed a forehand way long.
He must get past three-time champion Novak Djokovic in the semi-finals on Friday for another shot at the title.
Nadal soon returned the favour with a break of his own, before another hold left Del Potro rattled.
"I play Los Cabos in Mexico - the beach", he smiled.