Third-seeded Wawrinka will face a title clash with world number one Novak Djokovic.
Defending champion Djokovic beat France's Gael Monfils 6-3, 6-2, 3-6, 6-2 in New York to reach a seventh US Open final where he will be seeking a third major of the season and 13th of his career.
Wawrinka withstood an early onslaught from sixth-seeded Nishikori, asserting himself in the later stages despite the toll taken on both players in draining humidity on Arthur Ashe stadium court.
“It was tough conditions, it was really hot and humid so I knew it would be tough,” two-time Grand Slam winner Wawrinka said.
“It's crazy to be in the final.”
In contrast to Djokovic – who had a walkover and two matches shortened when opponents retired – Wawrinka has endured an arduous path to the title match, saving a match point in a fourth-set tiebreaker of a third-round victory over Briton Dan Evans.
In addition to that epic five-setter he had played three four-setters.
Coming into the semis he had spent 14 hours 47 minutes on court, a figure that swelled with his three-hour, seven-minute win over Nishikori.
Nishikori, coming off his own five-set quarter-final triumph over world number two Andy Murray, seized the initiative with a near flawless first set, breaking Wawrinka for a 3-2 lead and closing it out with an ace on set point.
He broke Wawrinka again to open the second, but the Swiss was gradually beginning to find his range and broke back to level the set at 2-2.
Trailing 0-40 in the seventh game, Wawrinka was able to save five break points to hold and knotted the match at two sets apiece with a break in the 12th game.
After taking the third and breaking Nishkori at love for a 2-0 lead in the fourth, Wawrinka appeared to be on his way.
But he found himself down 0-40 in the fifth game and after the Swiss saved two break points Nishikori had it back on serve when Wawrinka fired a backhand wide.
There was little respite for Nishikori. A quick break back and a hold at love and Wawrinka was back in charge.
“He dictated play early tonight, put pressure on me and gave me no time,” said the Swiss.
“I had to wait and fight and make him uncomfortable. He got tired and I started to be more aggressive.”
Wawrinka, who shocked Djokovic in the 2015 French Open final, was looking forward to his first US Open title title.
“I am really excited, I want to enjoy the moment,” he said. “I have seen the final here on TV many times, watching Roger, Rafa, Novak.”
Although Djokovic holds a 19-4 record over Wawrinka, including two victories since that Roland Garros surprise last year, Wawrinka welcomed the chance to take him on again.
“To play Novak again it will be very special,” he said.
The defeat ended 26-year-old Nishikori's hopes of improving on his runner-up finish to Marin Cilic in the 2014 final at Flushing Meadows.