Djokovic, the 2011 and 2015 US Open champion, will hae a chance to avenge his loss to Nishikori in the semi-finals in 2014- when the Japanese player finished runner-up to Marin Cilic.
Novak Djokovic reached his eighth U.S. Open final by beating Kei Nishikori 6-3, 6-4, 6-2.
"I don't know how it looked, but it felt really good", said Djokovic, who is aiming for a third US Open championship and 14th major title.
The 32-year-old Nadal quit during a match for the second time in four Grand Slams this year.
"One of the keys of the match will be [my] return, how well I can return, how many returns I can get back in play, but also try to have some depth in that return, and how accurately I can serve myself".
Djokovic missed the tournament past year because of an injured right elbow that eventually required surgery. You could imagine [it was] very hard for me to say goodbye before the match finished.
"That was not a tennis match at the end".
Djokovic, who was beaten by Nishikori in NY in 2014, improved his head-to-head record to 15 wins from 17 meetings with the victory after just two hours and 23 minutes.
That included nearly five hours to defeat Dominic Thiem in an epic quarter-final which stretched into the early hours of Wednesday morning.
Nishikori was content to stay at the baseline in the first set, and Djokovic dominated, breaking in the second game and often forcing Nishikori to overhit while on the run.
"Of course, it's not the best way to win a match".
"I'm very sad for him".
The No. 1-seeded Nadal has a history of tendinitis in his knees and he said he felt a problem in the right one early in the first set.
Comfortable breaks of serve came in each set as the dominant Serb cantered to victory to set up an enticing showpiece encounter with the hugely impressive Del Potro.
But the Argentine swept through the tiebreaker, wrapping up the opener after 69 minutes of impressive shot-making.
After the third game of the second set, he had a medical timeout so the trainer could massage his right leg and once again apply tape.
The third seed, who advanced after world number one Rafa Nadal retired from their match due to injury on Friday, said persistent wrist ailments almost led to him exiting the sport in 2015, what he called the "worst moment" of his career. But Nadal was so distraught after he pulled out of the match that he had difficulty saying he was pleased to see del Potro advance.
But he could not take either and, once Djokovic broke to lead 3-2, it merely seemed a question of how much resistance his opponent could muster.
"I didn't expect to get into another Grand Slam final", del Potro said. "I love to play against Rafa because he is the biggest fighter in the sport", Del Potro said. Now I'm much older.
WHAT IT MEANS: The US Open will crown a repeat men's champion on Sunday.