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.
Next up for the Spaniard is a blockbuster last four showdown with Novak Djokovic.
The Serbian is playing his best tennis for two years as he appears to have finally put injuries and poor form behind him. I tried to resist, maintaining focus.
Germany's Julia Goerges apologised after beating close friend Kiki Bertens to progress to the first semi-final of her career at Wimbledon.
But the 31-year-old has been rejuvenated at Wimbledon, sweeping into the semi-finals for the eighth time.
"I think I can move a little bit better than he can", Raonic said.
All four semi-finalists are aged 30 or over - the first time in the Open era that the men's singles semis at a Grand Slam have been contested exclusively by players over 30.
After a hectic clay-court season where he won the Monte Carlo, Rome and French Open titles, Nadal made a decision to go into Wimbledon without playing a warm-up event on grass for the second year running.
"I play Los Cabos in Mexico - the beach", he smiled. After the match, Nadal and del Porto embraced.
The pair have only met twice at Wimbledon, Nadal winning their 2007 semi-final when Djokovic retired hurt, the Serb gaining revenge in the 2011 final.
The Majorcan, who is the world number one but seeded second at Wimbledon, looked refreshed as he breezed through his opening four matches without dropping a set.
But Nadal was first to break in the deciding set and he built a 5-3 advantage with a looped forehand victor before confirming his final four place with a volley after four hours and 48 minutes.
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. "If I want to beat him, I have to come to the net very often and play hard with my forehands, with my backhands".
"I'm like, "You don't have to be sorry".
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