Nadal had had his right knee taped during his gruelling third-round clash against Karen Khachanov but insisted afterwards it was not a big issue and he appeared in good shape for his next two matches.
"Yeah, I waited as much as I can", said Nadal, who played 15 hours, 54 minutes on court in his first five matches, his most ever en route to a Slam semifinal.
"Of course, it's not the best way to win a match", said del Potro, who hugged Nadal when it was over.
The US Open men's semi-finals take place tonight in NY, and returning to preview the two matches, is our tennis columnist, Dan Weston. And while he still had the devastating forehand that's been one of tennis' signature shots and carried him to the 2009 title, repeated wrist injuries had made him one dimensional on the backhand side.
However, his condition notably deteriorated against Del Potro and a medical timeout early in the second set failed to bring the desired results for the Spaniard, forcing him to end the contest when trailing 7-6 (7-3) 6-2. "As you can imagine, it's very hard for me to say goodbye before the match finished", Nadal said afterwards, the news outlet reports. Nine years ago, he stunned Nadal in the semifinals, then Roger Federer in the final, to win the US Open at age 20.
It was the second time this year that the world number one has retired from a slam as he also quit during his quarter-final against Marin Cilic at the Australian Open in January.
"It's tough, these moments, but on the other hand I'm going to keep going and I'm going to keep working hard to keep having opportunities".
Djokovic has dropped only two sets en route to the final. Nishikori beat the Czech in their rematch in the quarter-finals this time.
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Del Potro will go on to face the victor of Novak Djokovic and Kei Nishikori, who play Friday night.
The Serb held comfortably and crafted five break points in the second game of the match, converting the fifth. He even barely took any time between points while serving - and he's known as one of the slowest guys on tour. "I still here. I still here because I love what I am doing", said Nadal.
An elbow injury in 2003 prevented his expected French Open debut that year and a stress fracture in one ankle kept him out of Roland Garros and Wimbledon in 2004.
Rafael Nadal insists he remains determined to fight for titles at the "highest level" after his US Open defence ended in retirement.
It's the 10th time del Potro has beaten the No. 1 player, so this isn't new ground for him.
Nadal has played 13 sets in his last three matches and it appears to have come at a cost.
Del Potro took the opening set after a brutal opening set went all the way to a breaker at Flushing Meadows, the Argentine taking it 7-3 with a series of stunning groundstrokes.