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.
Coming into this semi-final, he had already spent nearly 16 hours on court.
Nadal said that he first felt a knee problem in his second- or third-round match last week and that it acted up again Friday starting in the fifth game.
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.
"That was not a tennis match at the end. It was one tennis player playing, the other standing at the side of the court".
Del Potro was leading 7-6 (3), 6-2 after two hours of play Friday when Nadal shook his head and said he had to stop. "I was a kid then; now I am much older". "I hate to retire, but staying one more set out there, playing like this, would be too much for me".
The Serb has shown remarkable consistency in NY over the years, reaching the semi-finals on 11 occasions, although he has only converted two of his deep runs into titles thus far.
The reigning French Open champion ends his Grand Slam season having made it at least to the quarterfinals in all four majors. Lot of people in this room, including myself, never will think that at the age of 32 I will be here fighting for titles, fighting for the first positions of the rankings.
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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.
Djokovic, the victor in 2011 and 2015, faces Kei Nishikori in Friday's semi-finals, his 11th successive appearance in the last-four. But he was walking with a hitch in his step and had the trainer out to retape the knee early in the second set. "But at some point we had to take a decision".
With six years on the 37-year-old Swiss, speculation would no doubt mount as to whether 31-year-old Djokovic - who looks fit, healthy and motivated after a lengthy lay-off with an elbow injury - could even surpass his 20 major haul.
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.
This one, given the added difficulty created by unusually high heat and humidity, would certainly be meaningful. I'm still here. I'm still here because I love what I am doing.
Nadal tried to play through the pain but when Del Potro blasted a forehand victor to go ahead 7-6 (3) 6-2 the Spaniard removed his headband and said he could not continue.
The majority of the second set was largely played as a formality, with Nadal clearly not looking like himself.
While Djokovic has been able to routinely beat Nishikori in their previous meetings, Nadal and Del Potro have only met on four occasions since 2013. This is my favourite tournament, my biggest memories on a tennis court came on this court in 2009.