In a remarkable display of endurance, Nishikori followed up punishing five-set wins over third seed Stan Wawrinka and fifth seed Milos Raonic with an even more extraordinary effort, grinding down the top-ranked Djokovic in two hours, 52 minutes on a sweltering Arthur Ashe Stadium court.
"It's just amazing, an amazing feeling beating the number one player and also playing much better in these couple of matches so I'm so happy," the 10th-seeded Nishikori said.
"It was really tough conditions today, felt a little bit heavy and humid too but I guess I love to play long matches and I hope I can recover well for the final."
Nishikori denied Djokovic a fifth successive trip to the US Open final.
The 24-year-old Japanese awaits the winner of the second semi-final between world number two and five-times US Open champion Roger Federer and 14th seed Marin Cilic in Monday's final.
"I don't know what's going on," said Nishikori, who is coached by former grand slam champion Michael Chang. "I was a little bit tight; especially it was my first semi-final in a grand slam."
Djokovic was magnanimous in defeat.
"It was not easy to play in these conditions but also he had more hours spent on the court. So it's no excuse," the Serb said.
"I expected him to be able to play another five-setter because he had two days off.
"He just played better in these conditions than I did.
"I just wasn't managing to go through the ball in the court. You know, I wasn't in the balance. Unforced errors. Even when the ball gets back to his part of the court it's pretty short; he takes advantage of it. On the other side I didn't. That's it."
Nishikori arrived at sun-bathed Arthur Ashe Stadium looking fresh despite having played the latest finishing match ever at the US Open on Tuesday in the fourth round against Raonic, when he walked off court at 2:26 a.m. local time.
Two days later Nishikori was forced to go the distance again, out-lasting Wawrinka in a four hour, 15 minute battle.
But the biggest test of all came with gusting wind, stifling humidity and courtside temperatures hovering around 100 degrees (Fahrenheit), turning the semi-final into a survival of the fittest against a surging world number one who had dropped just one set on route to the final four.
Nishikori, appearing in his first grand slam semi-final, got the match off to a bright start by breaking Djokovic to go up 4-3 on the way to taking the opening set.
But the Wimbledon champion upped his game in the second, dominating play with a pair of breaks before finishing off the set with a thundering ace.
The battle intensified in the third as the two men, sweat pouring off them, exchanged breaks to send the set to a tiebreak.
Nishikori took the initiative, racing to a 4-0 lead before Djokovic staged a rally but could not wrestle the advantage away from the Japanese dynamo who went on to claim the breaker 7-4.
The tiebreak appeared to give Nishikori a huge boost, the 10th seed returning to court and immediately breaking the Serb to take control of the set.
"He (Djokovic) started to play much better, very consistent and being more aggressive," said Nishikori. "I tried to forget about the first and second set and tried to concentrate again.
"I hope it's big news in Japan. I feel the support from Japan even from the TV even though it's 4 o'clock in the morning but I hope a lot of people watching." (Editing by Gene Cherry)