The 23-year-old Keys beat Suarez Navarro in straight sets, 6-4, 6-3.
Djokovic has now won all 11 of his quarterfinal matches in NY.
Nishikori, the 21st seed, advanced with a 2-6, 6-4, 7-6 (7/5), 4-6, 6-4 victory over Marin Cilic - the man who beat him in the 2014 final.
It has already been a successful return to Flushing Meadows for Nishikori who missed the U.S. Open past year with a wrist injury that saw his ranking plunge and put him on the comeback trail that included playing Challenger-level tournaments. "Just trying to hang in there, trying to find a way to win the match".
Beforehand recognized tennis participant was named the favorites for the US Open event.
The Serb, who ended a 54-week title drought with his 13th grand slam title at Wimbledon, defeated the tenacious Aussie 6-3, 6-4, 6-4 to reach his 11th US Open semi-final in his last 11 appearances.
By Paul NewmanWhere Roger Federer failed, Novak Djokovic prevailed.
The Japanese sputtered along until earning his first break chance at 2-4 in the second set and was able to convert to get back on serve.
Even in the final set Nishikori looked comfortable with a 4-1 lead before Cilic levelled, only for the Croat to lose the final two games.
Meanwhile, Australian Open champion Caroline Wozniacki called out supporters in the stands at the Miami Open earlier this year for abuse suffered by both her and her supporters in her player box.
Keys, who at 14 is the highest seed left in the women's draw, has shown a determination to go one step further than previous year, having only dropped one set through her four matches.
"I personally have never sweat as much as I have here".
"It's great to see, " said Nishikori, who is into his third major semifinal - all in NY - but is still in search of his first Grand Slam trophy. She won the Indian Wells Open and made it to the fourth round of the Australian Open. That break seemed to give Djokovic some much-needed rest and he sat down on his sideline bench without a shirt on and cooled off.
"I was struggling. He was struggling", Djokovic said.
"He just has to bring it again", Federer said, adding that Millman's intensity was a difference maker in his four-set defeat.
"I was very tested", Djokovic said.
She raced to a 3-0 lead in the first set and then 4-0 in the second against the shaky Tsurenko, who finished with more unforced errors than points in her first major quarterfinal. That was at Wimbledon in 1995, and both Shuzo Matsuoka and Kimiko Date lost in that round.
"I was struggling, he was struggling, we were all sweating, changing clothes".
"I can only talk about myself", Djokovic said.
Nishikori stunned then-world No 1 Djokovic in the semi-finals in 2014 to become the first man from an Asian country to reach the championship match of a major. "John is never going to hand you the win".