Nishikori became the first Japanese man for almost a century to reach the US Open semifinals after securing an epic 3-6, 7-5, 7-6 (9/7), 6-7 (5/7), 6-4 win over Wawrinka.
The 24-year-old Japanese triumphed in four hours 15 minutes, his second marathon clash after needing four hours 19 minutes to get past Milos Raonic in the previous round.
On Saturday Nishikori will face world number one Novak Djokovic, who triumphed over Brit Andy Murray in the early hours of Thursday morning, for a place in Monday's championship match.
Ichiya Kumagae was the last Japanese man to reach the semi-finals of the US Championships in 1918.
Nishikori, whose match against Raonic ended at a record-equalling 2:26am on Tuesday, was stunned by his win over Wawrinka, the Australian Open champion who had won the pair's two other meetings without dropping a set.
"I was tight at the start but my body was OK. I felt more confident after the first set," said Nishikori, who will be playing in his first Grand Slam semifinal having made the quarterfinals in Australia in 2012.
"It feels amazing. I am playing well and I hope to play at 100 percent in the semifinals."
Nishikori stands at 1-1 against Djokovic and trails Murray 3-0 having lost to the Briton in the quarterfinals in straight sets in Melbourne two years ago.
Wawrinka praised the stamina of Nishikori who has now spent more than 13.5 hours on court at the tournament.
"From outside he looks really dead, but we know on the court he can play," he said.
"Physically he's there, even at the end of the match. I still think that I was the fresher on the court, but he handled it well."