Japan's fifth-ranked Nishikori rallied to beat Australian James Duckworth 6-7 (8/10), 6-1, 6-4 while Croatia's eighth-ranked Cilic defeated 77th-ranked South Korean teen Chung Hyeon 7-6 (7/2), 6-3 in their first hardcourt appearances on the road to this year's US Open.
"It wasn't easy to put him away," Cilic said. "He's a great counterpuncher."
Cilic, the first reigning US Open champion to play in the US capital since Andre Agassi in 2000, and second seed Nishikori each had first round byes and saw their matches pushed into the wee hours by a rain delay.
Next in Nishikori's path will be the winner of a Wednesday match between Argentina's Leonardo Mayer and Slovenia's Blaz Rola.
The 25-year-old Asian number one, playing his first match since pulling out of Wimbledon in the second round with a calf injury, fought back after dropping a tense tie-breaker to seize command of the match.
"From the second set I started playing better, less unforced errors, more aggressive," Nishikori said.
In his first match since a Wimbledon quarter-final loss to eventual champion Novak Djokovic, Cilic surrendered a break in the seventh game but broke back in the eighth.
In the tie-breaker, Cilic jumped ahead 6-1, double faulted, then blasted a service winner to win the set after 53 minutes, taking all 18 of his first serve points in the set.
"The important part was to get the ball back and put the first serve away," Cilic said.
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