The warning signs were there from the moment when Nadal called the trainer on to the court to apply tape to his cranky right knee, which has been an issue since his third-round match against Karen Khachanov.
Nadal said he didn't know what kind of effects might have been lingering from his quarterfinal victory over Dominic Thiem, which lasted five sets and almost five hours.
Nadal's challenge looked doomed even as early as the first set, feeling the injury after just four games, he admitted.
Over and out: Rafael Nadal, of Spain, waves to fans after retiring from the match.
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. It was just one player playing, the other one staying on the other side of the court.
The three-time champion retired at the end of the second set with Del Potro leading 7-6 (7-3) 6-2 on Arthur Ashe.
"I waited as much as I can", said Nadal. The two that preceded the Wimbledon classic were easier victories, a semifinal rout en route to the French Open title and a four-set victory in last year's U.S. Open semifinals, when Nadal dominated the last three sets.
The 17-time Grand Slam champion also reached the quarter-finals of the Australian Open this year, as well as the semi-finals at Wimbledon. "I will be proud if I (am) still playing tennis for more years".
An eighth final is within reach and to achieve that, the 31-year-old expects Nishikori to make him sweat - literally.
Grimacing with every sudden move, the 17-time Grand Slam victor called for the trainer during the changeover on serve at 2-1 in the second.
The world number one had been targeting a fourth US Open title, but instead it's Del Potro who is eyeing his second after winning the title back in 2009.
After edging a 69-minute set, Del Potro applied pressure early in the second, thundering winners off both wings to get to 15-40 in game two.
He has resurrected his career impressively after minor surgery on his long-term elbow injury, which kept him out of the game for six months past year.
Nadal, who had never before retired from a U.S. Open match, showed signs of distress nearly from the start as he limped noticeably after a grueling 69-minute opening set.
It's the 10th time del Potro has beaten the No. 1 player, so this isn't new ground for him. "You could imagine very hard for me to say goodbye before the match finish but at some point you have to take a decision".
Del Potro returns to the final: Nine years after he shocked the tennis world by taking out Roger Federer in the 2009 final, del Potro is back in the Sunday showcase.
"It means a lot to me", del Potro said. "I had my biggest memories on the tennis court playing on this court ... but I was a kid".