Of the 61 first serves he landed in, he won 52, and was broken only three times en route to a 6-3, 3-6, 6-2, 6-2 win over the 2014 US Open finalist.
Next up for the Spaniard is a blockbuster last four showdown with Novak Djokovic.
A set littered with one lengthy rally after another, eventually went to Nadal on serve, finally giving him the match.
With the Wimbledon lawns baked and playing more bouncy than usual after a long spell of hot weather in London, it could be the 29-year-old's best chance to stop Nadal's impressive run.
As Nadal looks ahead to the semi-finals, Del Potro heads for his next tournament.
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"Beating Roger Federer at Wimbledon is definitely one I'm going to remember". However, I am utterly shocked that the markets are finding it hard to split Nadal and today's opponent, Novak Djokovic, for the second semi-final, which will commence no earlier than 1500 United Kingdom time. He's one of the most complex players I ever saw in our sport. "I really do. I think with the performances I've had, I deserve to be in the semifinals", he continued. Simon failed to convert a break point, then a third match point for Del Potro ended with him netting a forehand.
"Sometimes you play your best tennis and it's not enough to beat him", said the teary-eyed Argentine, who has had the misfortune of running into Nadal at the French Open and Wimbledon championships over the past five weeks.
"For the rest of the things, great news, semi-finals of Wimbledon again".
Isner, 33, will be playing in his first major semi-final and is bidding to become the first American man to reach a Slam final since Andy Roddick finished Wimbledon runner-up in 2009.
While both of those Nadal victories came on clay, they may set the tone for how this match begins.
'In the same time, I'm trying to use the experience and memories that I had on being in final stages of Grand Slams, just take things very simple, day by day. His US Open win a year ago was the first time he had won a Grand Slam outside of the French Open since winning the US Open in 2013. "He's playing well. Only way to try to win it is (to) play very well". Nadal was back to needing one game to claim the set. "I felt like I did some good business here in the past already", he said. I'd guess that Rafa will have more self-belief than Djokovic in the early going.