The big-hitting Croatian, fresh from dominating Roger Federer in his semi-final win, had few problems in a 6-3 6-3 6-3 victory over Japan's Nishikori at Flushing Meadows.
Cilic's serving was consistent throughout the one hour 53 minutes and Nishikori struggled to make inroads.
With both in their first grand slam finals, only the 25-year-old 14th seed rose to the occasion in New York as he hit 38 winners and 27 unforced errors.
He became the first Croatian to win a grand slam since his coach, Goran Ivanisevic, managed the feat at Wimbledon in 2001.
Nishikori, who held a 5-2 win-loss record over Cilic coming into the clash, finally looked lethargic as he failed to match his opponent's power and depth.
The 24-year-old 10th seed had enjoyed five-set wins over Milos Raonic and Stanislas Wawrinka before his upset last-four victory against world number one Novak Djokovic.
Nishikori had a chance to make the perfect start with a break point in the opening game, but that was saved by a powerful cross-court winner from Cilic.
It would be a moment Nishikori – the first Asian man to reach a grand slam singles final – would rue more than most expected.
Nishikori would win just four return points for the set and his errors handed Cilic the only break in the sixth game.
Cilic hit 11 winners for the set, but his opponent's nine unforced errors – Nishikori finished with 30 – were decisive.
Making matters worse for Nishikori, he was broken in the third game of the second set before Cilic battled from 15-40 down to hold for 3-1.
A Nishikori forehand into the net saw Cilic go 5-2 up before the Japanese right-hander broke for the first – and only – time in the eighth game.
But a long point in the ninth game led to a Cilic forehand down-the-line winner as he took a two-sets-to-love lead.
When Nishikori dragged a cross-court backhand wide to give Cilic a break in the fourth game of the third set, there was no way back.
With a burst of energy, Nishikori tested Cilic in the seventh game, but the latter responded and held for 5-2 with a powerful backhand winner.
Just like against Federer, Cilic showed few nerves in closing out the match as a pair of big serves, a Nishikori error and finally – a backhand winner – saw him to the title.
If his win over Federer was the best performance of his career, this was the best moment.