The victory also completed a historic day for Japanese tennis, with Naomi Osaka routing Ukraine's Lesia Tsurenko 6-1 6-1 and the pair became the first Japanese man and woman to reach the semi-finals of the same grand slam.
"It's great to see," said Nishikori. "I think she can win a title now, even though grand slam. I feel it is a big chance for her. I am also happy for myself."
It was a much different outcome from 2014 when the big-hitting Cilic floored the Japanese counter-puncher 6-3 6-3 6-3 to claim the US title.
Cilic has made two grand slam finals since but Nishikori has never been back and will now take on either twice US Open champion Novak Djokovic or unseeded Australian John Millman for a spot in Sunday's final.
It has already been a successful return to Flushing Meadows for Nishikori, who missed the US Open last year with a wrist injury that saw his ranking plunge and put him on the comeback trail that included playing Challenger-level tournaments.
But after reaching the final in Monte Carlo, the French Open fourth round and the Wimbledon quarter-finals, Nishikori believes an elusive first grand slam is within reach.
"Yeah, always excited to play Novak because it's great challenge for me," said Nishikori about the possibility of facing Djokovic, should the sixth-seeded Serb beat Millman in the quarter-finals.
"Always exciting to play him. Especially after coming from injury, I think I'm enjoying this challenge."
Initially, it looked like the match might follow a similar storyline from 2014 when seventh seeded Cilic took the opening set from a sluggish Nishikori.
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.
As Nishikori began to find his rhythm Cilic started to misfire and the Japanese 21st seed collecting a second consecutive break on a double fault to surge in front 5-4 before holding serve to level the match.
The tide continued to turn in the third as Nishikori chipped away at the faltering Cilic with a third successive break.
Cilic did level at 4-4 but his erratic play continued as Nishikori stole the set with the help of two double faults in the tiebreak.
The Croat rebounded to take the fourth and the rollercoaster ride continued into the fifth with Nishikori grabbing the advantage with a break at 3-1 and taking Cilic's serve again with a blistering return winner to close out victory.
Naomi Osaka enjoyed a comfortable 6-1 6-1 win over Ukraine's Lesia Tsurenko to become the first Japanese woman in 22 years to reach the semi-final stage of a Grand Slam.
The 20th-seeded Osaka, a rising talent who won her first career title in March at Indian Wells, used a lethal ground game and solid serving to overwhelm a fatigued Tsurenko, who laboured in stifling conditions on the Arthur Ashe Stadium court.
Osaka, the first Japanese woman to reach a Grand Slam semi-final since Kimiko Date at Wimbledon in 1996, broke Tsurenko five times during a match that only lasted 57 minutes.
The 20-year-old Osaka, who has looked comfortable on one of the sport's biggest stages, was tearful after her fourth-round clash but much less emotional after her latest win.
"The other time I cried a little bit and there was a lot of people making fun of me," Osaka said during her on-court interview. "I was freaking out inside, just like my whole body was shaking, so I'm really glad I was able to play well."
