The Croat clinched his maiden grand slam success with a 6-3 6-3 6-3 win over Nishikori at Flushing Meadows, netting $3,000,000 in prize money.
Victory sees Cilic, who was ranked 16th at the start of the tournament, climb to ninth in the world rankings.
It is the first time the big-serving 25-year-old has featured inside the top 10 since April 2010, when he was also ranked ninth.
In addition, Cilic moves from 13th to fifth in the ATP Race to London, which will decide the eight-player line-up for the World Tour Finals in November.
Nishikori's run to the final sees the Japanese rise from 11th in the ATP rankings to eighth, and four places to sixth in the Race to London.
Two-time major winner Andy Murray drops to 11th - the first time the Scot has been outside the top 10 since June 2008.