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.
The world number one had spent more almost 16 hours on court in reaching the last four, averaging more than four hours a match during the last three rounds, and that took its toll here.
"I think it was two-all in the first, 15-love, something like this in the first set, that I felt (something)", said Nadal.
Nadal, the defending U.S Open champion, was trailing 7-6, 6-2 when a knee problem forced him to stop after nearly two hours of playing time. He'll attempt to win his second U.S. Open title nine years after he defeated Rafa Nadal then Roger Federer to win his only career major title. He's made the French Open semifinals, the Wimbledon quarterfinals, and now a US Open final this year. I going to keep fighting and working hard to keep enjoying this tour and keep having chances to compete at the highest level.
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.
"Negative thing is two of them have been in quarter-finals and semi-finals of a Grand Slam, close to fight for titles". Incredible. I mean, I have to take at least 10 shirts for every match.
After failing to make much attempt to reach a dropshot he summoned the physio and took a medical timeout at 2-1 down in the second.
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On Sunday, the powerful Argentine with the massive forehand that zips along at more than 100 miles per hour will face two-time US Open champion Novak Djokovic, who defeated Kei Nishikori 6-3, 6-4, 6-2 in the second semifinal Friday night.
He called for the trainer during the changeover on serve at 2-1 in the second.
The majority of the second set was largely played as a formality, with Nadal clearly not looking like himself. "You could imagine very hard for me to say goodbye before the match finish but at some point you have to take a decision".
He will have a shot at the hat-trick on Sunday, though, when he comes up against 2009 champion Del Potro.
Djokovic missed last year's tournament owing to an elbow injury.
One of the greatest players of all time, the one chink in the Spaniard's armour has always been his knees with injuries plaguing him throughout his career.
"I feel that this tournament, Juan Martin is hitting a little bit bigger off his backhand". "I had my biggest memories on the tennis court playing on this court ... but I was a kid".