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.
Although Nadal has the edge when it comes to head-to-head meetings, all five of Del Potro's victories have come on hard courts where his flat forehands are at their most effective and he will look to utilise that weapon as much as possible.
Nadal's challenge looked doomed even as early as the first set, as he was feeling the injury after just four games, he admitted.
Rafael Nadal of Spain waves to the crowd after retiring from a men's semi-final match against Juan Martin Del Potro of Argentina on day twelve of the 2018 U.S. Open tennis tournament at USTA Billie Jean King National Tennis Center. "But it was not a tennis match at the end".
"As thousands of other tennis players around the world, I'm trying to be the best I can be", Djokovic said immediately after beating Nishikori.
The Spaniard was simply unable to recover and had his knee attended to again in the second set as Del Potro marched through to take it 6-2 with minimal trouble. "I know what is going on with the knee". Nine years ago, he stunned Nadal in the semifinals and Roger Federer in the final at the U.S. Open at age 20.
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.
"It was hard for me to keep playing".
He has won the last 13 although Nishikori defeated the Serb in NY in the 2014 semi-finals on his way to a runners-up spot against Marin Cilic. For him will be huge if he's able to win again a Grand Slam'.
Twice champion Djokovic, who reached his eighth final at Flushing Meadows and is seeded sixth this year, broke Nishikori in his first service game and closed out the opening set with an ace in 37 minutes without facing a break point. He was visited by a trainer at the changeover after the match's seventh game and tape was applied below the joint.
This one, given the added difficulty created by unusually high heat and humidity, would certainly be meaningful.
It's the 10th time del Potro has beaten the No. 1 player, so this isn't new ground for him.
"I love to play against Rafa because he's the biggest fighter", del Potro said after the Nadal left the court.
It took Nishikori more than a quarter of an hour to get on the board on Friday, but, on a night when injury was the talking point, he pulled up dramatically mid-point in the ninth game, grabbing at his right leg, before holding to keep the set alive at 3-5.
Nadal, who reached the last four in NY on the back of brilliant shot-making and incredible movement, looked out of sorts early against Del Potro and struggled to cover the court with his usual tenacity.