Del Potro, who lost to Nadal in last year's semi-finals, said he was now focused on extending his career, sticking to a daily yoga regime and spending hours on treatments for his wrist and body.
Novak Djokovic stayed on course for back-to-back grand slam titles by beating Kei Nishikori to set up a US Open final against Juan Martin del Potro.
The sixth seed will contest an eighth US Open final looking for his third title and 14th overall at slams, which would put him level with Pete Sampras.
Djokovic missed last year's tournament owing to an elbow injury.
Nadal said he did not sense a return of his chronic knee tendinitis on Thursday when he practised, or warming up before the match. "That is all", Nadal said in a post-match press conference.
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"It was not a tennis match at the end". He has won the last 13 meetings, such a run of dominance that the Japan native didn't recall that he beat Djokovic in Flushing Meadows in the 2014 semifinals, adding that maybe he should rewatch the match.
Nadal's stamina and famous fitness have been put to the test on the sweltering Flushing Meadows hardcourts as he has logged almost 16 hours through five matches.
"I was putting constantly pressure on him, trying to move him around the court, take away the rhythm from him, not give him the same look always. Yeah, I didn't have [the] energy to stay with him", Nishikori said.
Nadal, who reached the last four in NY on the back of brilliant shot-making and incredible movement, looked out of sorts early against Del Potro and struggled to cover the court with his usual tenacity.
But the Argentine swept through the tiebreaker, wrapping up the opener after 69 minutes of impressive shot-making.
While leading 4-3 in the first set Nadal got his right knee taped, before later ripping it off and having it re-taped early in the second during a medical timeout in which he also had his leg massaged.
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Nadal suffered a recurrence of his persistent knee injuries during a gruelling third round victory against Karen Khachanov and the problem became worse during the first set on Friday.
As del Potro continued slamming serves at faster than 130 miles per hour (210 kph), whipping that trademark forehand and even making hay with his much-improved two-handed backhand, Nadal offered less and less resistance.
But he could not take either and, once Djokovic broke to lead 3-2, it merely seemed a question of how much resistance his opponent could muster.
"I personally like him very much, not just as a player but as a person", said Djokovic of Del Potro.
"I didn't expect to get this kind of emotions playing tennis again".
"He's a big match player and I'm sure the final will be a thrilling match".
US Open semi-finalist Sevastova stays in the moment
Stephens said that despite the manner of her defeat on Tuesday she was content with what she had achieved at this tournament. Pliskova defeated Williams in the semifinals in 2016 before losing to Angelique Kerber in the final.