Wawrinka dropped the opening set in a hot and humid Arthur Ashe Stadium but the world No 3 battled back to win 4-6 7-5 6-4 6-2 and reach his third Grand Slam final.
He will now meet defending champion Djokovic on Sunday in a repeat of the 2015 French Open, when Wawrinka stunned the Serb to clinch his second major title.
Roger Federer was beaten by Djokovic in the final here 12 months ago but with the 17-time Grand Slam champion injured and absent from Flushing Meadows, it is another Swiss now hoping to get his hands on the trophy.
“I knew it would be really tough to beat Kei,” Wawrinka said.
“He was playing very good from the beginning, dictating, not giving me any time to get my game. I had to wait, fight, try to make him more uncomfortable.
“He also started to get tired a little bit and that’s when I started to get my game, to be aggressive.
“I’m happy, it was an amazing atmosphere and to tell myself I’m going to be in the final is something crazy.”
Wawrinka’s triumph at Roland Garros was the only time Djokovic has lost a major final in his last seven appearances at that stage and the 31-year-old may need a performance of similar magnitude if he is to manage a repeat.
“I am really excited, I am really happy, I want to enjoy the moment,” Wawrinka said.
“I watch the finals here so many times – Roger, Novak, Rafa (Nadal) – they areamazing champions and to be play against Novak, last year at the French, we play so many matches at a grand slam so to play him is something special.
“I am always ready when I’m happy on the court so let’s see what’s going to happen.”
Nishikori produced a dynamic, steely display to knock out Andy Murray in the quarter-finals on Wednesday but the sixth seed may have felt the after-effects of that encounter as he struggled with cramp in the latter stages.
Wawrinka was match point down against Britain’s Dan Evans in the third round in New York but a kind draw has allowed him to find his stride and he will be a dangerous opponent this weekend.
He won 70 per cent of first serve points in the last two sets and hit 38 winners overall.
In sweltering conditions reaching 70 per cent humidity, Nishikori’s athleticism looked set to prove a major advantage and it was the Japanese who started stronger, breaking at 3-2 and serving out the opening set.
Nishikori had taken the game to his opponent, following up his groundstrokes with regular forays to the net but he was less clinical in the second and allowed Wawrinka to grab a foothold.
Seven break points came and went for Nishikori, including two at 4-4, and Wawrinka made him pay by pouncing on his own set point at 6-5.