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.
Coming into this semi-final, he had already spent nearly 16 hours on court.
Nadal's challenge looked doomed even as early as the first set, feeling the injury after just four games, he admitted. "It was not a tennis match at the end". "Like thousands of other tennis players around the world I'm trying to be the best I can be".
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.
After having his right knee taped, Nadal threw in a sloppy game to be broken again at 4-4, giving Del Potro the chance to serve out the opener.
The slower courts, oppressive weather and a long succession of arduous matches took a heavy toll on Nadal, who also pulled out of his Australian Open quarter final in January when he was behind to Marin Cilic. I going to keep fighting and working hard to keep enjoying this tour and keep having chances to compete at the highest level.
Novak Djokovic of Serbia celebrates victory following his men's singles semi-final match against Kei Nishikori of Japan on Day Twelve of the 2018 U.S Open on September 7, 2018 in New York City. Yes, it is bitterly disappointing but he has added another Grand Slam title in 2018 and he is world number one. "[Today] at 2-all in first set, I told my box I felt something in my knee".
Nadal survives Thiem test to reach semis, Stephens ousted
Pliskova is the last woman to beat Williams at the US Open , eliminating her in the semifinals two years ago. This is her first win against a top-10 player since returning from maternity leave.
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 love to play against Rafa because he's the biggest fighter in this sport and I don't like to see him suffering", said 29-year-old Del Potro who will be playing in his second Slam final.
The No. 6-seeded Djokovic missed last year's tournament with an injured right elbow.
Del Potro, who has returned to the pinnacle of the sport after recovering from two wrist surgeries in 2010, had lost to Nadal the last three times the players had met in grand slams and had lost 11 times from 16 meetings against the Spaniard.
Del Potro sensed blood and broke for 3-1 as Nadal struggled for movement. This is my favourite tournament, my biggest memories on a tennis court came on this court in 2009.
That hasn't stopped him amassing 17 Grand Slam titles, three short of Swiss great Roger Federer's record 20.
The Argentine has also beaten Nadal at this stage of the US Open before - a commanding 6-2, 6-2, 6-2 victory on his way to the title in 2009.