He lifted the trophy in 2011 and 2015.
Cilic triumphed in straight sets four years ago, but Nishikori gained a measure of revenge on Wednesday by edging a seesaw contest 2-6 6-4 7-6 (7-5) 4-6 6-4 after four hours and eight minutes.
It wasn't the cleanest of matches as the grueling heat at Arthur Ashe Stadium seemed to force both competitors into a slew of mistakes over the course of the four-plus hour match.
He will play either Serbia's Novak Djokovic or Australian John Millman in the last four.
They applauded Millman's drive to come back from major injuries and early-career struggles - and then likened the fans missing out on Federer-Djokovic to seeing an understudy take the stage on Broadway.
Should Williams beat Osaka - the first Japanese woman to advance to a Grand Slam final - she will equal Margaret Court's record of 24 Grand Slam singles titles.
That made it all the more surprising that the 28-year-old allowed his advantage to slip, missing a break point that would have given him a 5-1 lead and then being pegged back to 4-4.
Nishikori's relatively week serve could be the deciding factor here, as if Cilic can get into his groove he will look to punish that aspect of his opponent's game, especially the second serve.
Naomi Osaka, of Japan, returns a shot to Lesia Tsurenko, of Ukraine, during the quarterfinals of the U.S. Open tennis tournament, Wednesday, Sept. 5, 2018, in NY.
She's the most inspiring person I know
She is also the second Japanese player to reach a Grand Slam singles final after Kei Nishikori, who lost in the final of the U.S. In fact she closed it out with a service victor that bounced wildly off the frame of Keys's racquet.
Beforehand recognized tennis participant was named the favorites for the US Open event. But Millman scuttled that showdown by stunning the 20-time Grand Slam champ in four sets in the fourth round on a hot and humid evening that Federer said sapped his energy and made it hard to breathe.
The Serbian star, 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 semifinal in his last 11 appearances.
Djokovic broke early to take a 3-1 leave in the third set but a lapse in concentration allowed Millman to draw level.
"Naomi's doing well, because she has won a Masters (Indian Wells in March)".
"He doesn't miss a lot himself, so he just runs left, right, gets a lot of balls".
Both players hit comfortably more unforced errors than winners with Cilic making 70 unforced errors to 57 winners and Nishikori 45 to 29.
The crisis soon deepened for Tsurenko, who had needed the best part of three hours on Monday to beat Czech teenager Marketa Vondrousova in a match where she nearly collapsed due to heat exhaustion. He fended off seven break points but couldn't stop Djokovic from converting on the eighth to take the two-sets to one lead.
This time, Keys will play No. 20 Naomi Osaka Friday for a chance to reach the final again.
The American fired 22 winners and six aces past Suarez Navarro who had knocked out former champion Maria Sharapova in the previous round. I'd play in a swimming pool if I got to play a quarter-final every week at a Grand Slam.