After Naomi Osaka reached the women's semi-finals earlier, Nishikori's win means there is a Japanese man and woman in the last four of a Grand Slam for the first time in the Open Era. Osaka routed Lesia Tsurenko 6-1, 6-1 in just 57 minutes, the third time in her five matches in the tournament that she finished in less than an hour.
Cilic made a dominant start to lead by a set and a break before his level dropped to allow Japan's Nishikori to take a 2-1 lead.
When Nishikori became the first Asian male to reach a Grand Slam singles final four years ago, hundreds of fans packed into a convention hall to cheer him on at a standing-room-only public viewing event in his hometown of Matsue.
She purported to be "freaking out inside", even if it certainly never showed.
"To break in both sets, having solid games there, was really important tonight", Keys said in her on-court post-match interview.
Osaka, the daughter of a Japanese mother and Haitian father, said she enjoyed playing in the blistering heat of NY which has been such a talking point of the tournament.
The seventh-seeded Cilic won the 2014 final in straight sets for his only career major title.
Keys, the runner-up to Sloane Stephens previous year, took her record over Suarez Navarro to 4-0 thanks to a break in the ninth game of the first set and sixth of the second.
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"Today was not my day, obviously", Tsurenko said.
"I think I'm enjoying this challenge".
"I felt like I had a lot of chances to break her in the third set, then she would serve these really incredible serves". "I feel a lot of support, and I'm really grateful about that".
Osaka's first serve percentage was only 59 percent but she did not concede a point behind her first serve the entire first set and only surrendered seven points on serve over the match.
The two are power hitters of the same cloth but different countries and it was Osaka who prevailed giving Sabalenka a taste of her own medicine first.
She pushed some balls a few feet past the baseline, often failing to make Osaka do anything special to win a point and finishing with 31 unforced errors. She recovered to win in three sets, with her opponent accusing her of acting after the match.
Tsurenko didn't appear bothered by the conditions, but whether it was her health or just first-time jitters, she was off from the minute she stepped onto Arthur Ashe Stadium.