But he had a knee issue earlier in the tournament, when he had it taped during his victory against Karen Khachanov in the third round.
Nadal's challenge looked doomed even as early as the first set, feeling the injury after just four games, he admitted.
"Of course, it's not the best way to win a match", said del Potro, who hugged Nadal when it was over.
"That was not a tennis match at the end, no?"
"I hate retiring but to stay one more set out there playing like that is too much for me", said Nadal.
Del Potro was leading 7-6, 6-2 at the time of Nadal's retirement, and will now play his first major final since he won the title here in 2009.
"I waited as much as I can", said Nadal. After losing the first three matches of his comeback this year, he has gone on to reach the quarter-finals at Roland Garros, lose to Nadal in the semi-finals in Rome and in the Queen's final to Cilic, before beating Kevin Anderson in the Wimbledon final. But at the same time I have to keep going and working hard to get more opportunities.
"I'm having two great years", added Nadal, who was trying to complete a French Open-US Open double for the second straight season. A lot of people in this room, including me, didn't think I would be at this level at this age.
But he took a medical time-out after three games of the second set and, as he limped around the court, it became increasingly clear that he was in serious trouble.
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Novak Djokovic, of Serbia, celebrates after defeating Kei Nishikori, of Japan, during the semifinals of the U.S. Open tennis tournament, Friday, Sept. 7, 2018, in NY.
"I was close to quit this sport because I couldn't find a way to fix my wrist problems".
Djokovic, who was forced to skip last year's tournament due to an elbow injury and returned to the tour this year after surgery, said he was thrilled to be back on the big stage.
Nishikori began the third set with a confident hold of serve but the 28-year-old made four unforced errors in his next service game to set Djokovic on the road to victory. "But at some point we had to take a decision".
Reaching a second consecutive Grand Slam final suggests the 13-times major champion is almost back to his best, though he will need to be even more clinical against Del Potro, who has only dropped one set in six matches in NY.
Many experts have long felt Nadal's physical style of play, which relies on power and athleticism in contrast to his more graceful rival Roger Federer, puts him more at risk of injury.
It's the 10th time del Potro has beaten the No. 1 player, so this isn't new ground for him. "I had my biggest memories on the tennis court playing on this court ... but I was a kid".