A weary and wounded world No.1 Rafael Nadal has retired from his US Open semi-final while trailing Juan Martin del Potro 7-6 (7-3) 6-2, sending Del Potro back to the Flushing Meadows final for the first time since his 2009 triumph.

Argentina's Del Potro will face a ruthless Novak Djokovic, who beat Kei Nishikori 6-3 6-4 6-2 in the other semi-final to reach his eighth final at Flushing Meadows.

Earlier, Nadal showed signs of distress almost from the start as he limped noticeably after a gruelling 69-minute opening set.

Del Potro consoles Nadal. (AAP)

Grimacing with every sudden move, the 17-time Grand Slam winner called for the trainer during the changeover on serve at 2-1 in the second.

The defending champion had his knee massaged and re-taped and continued through the second set before telling the umpire he was unable to continue.

"I think it was two-all in the first, 15-love, something like this in the first set, that I felt (something)," said Nadal. "I said to my box immediately that I felt something on the knee.

"After that, I was just trying to see if in some moment the thing can improve during the match.

It's the second time this year Nadal has retired in a Grand Slam. (AAP)

"But no, was not the day.

"I waited as much as I can. You could imagine very difficult for me to say goodbye before the match finish but at some point you have to take a decision."

It was the second time this year that Nadal has retired from a slam as he also quit during his quarter-final against Marin Cilic at the Australian Open in January.

"This year have been a fantastic year until this moment," said Nadal. "I lost four matches. Two of them I had to retire ... in quarter-finals and semi-finals of a grand slam."

Del Potro, who has also had his career disrupted by injuries, was not happy to get the victory the way he did.

Djokovic was strong in advancing. (AAP)

"It's not the best way to win a match," said Del Potro.

"I love to play against Rafa because he's the biggest fighter in this sport. I'm sad for him."

Meanwhile, Djokovic needed just two hours and 22 minutes to dismiss Nishikori, seeded 21st, as he increased his head-to-head record over him to 15-2.

"It felt great. I thought I came in today right out of the blocks with a great intensity," Djokovic said.

Nishikori said he was happy to have made it to the semi-finals.

"I was (trying) to give 100 per cent, but he was playing very solid," he said. "Maybe if he wasn't Novak, I might have (a) chance to play [a] little better.

"It wasn't easy to stay with him tonight."