2014 champion Cilic finds himself in the quarter-finals at the US Open for the fifth time and was particularly impressive in his fourth-round victory over David Goffin, although his opponent played for a significant portion of that match with an injury.
Cilic can draw upon the experience of having beaten Nishikori twice at Flushing Meadows, the most notable of which was his victory over the Japanese player in the 2014 final.
The Croat has saved some of his best tennis for Grand Slams in recent times having reached the final of the Australian Open this year and also at Wimbledon last year so he will not be lacking in self-belief that he can go further.
Nishikori has only dropped one set on his way to the quarter-finals and was relatively comfortable in his 6-3, 6-2, 7-5 win over Philipp Kohlschreiber in the fourth round.
Despite a losing record against Cilic at the US Open, Nishikori does lead their overall head-to-head and was the victor in their only meeting in 2018 so far - a 6-4, 6-7, 6-3 win in Monte Carlo on clay.
The Japanese star has now reached the quarter-finals of the last two majors and this represents a return to the big time after his injury problems at the end of 2017 and the beginning of this year.
This will be the fourth meeting between these two at the US Open and their 15th overall, and it has been a rivalry often decided by narrow margins. Their contrasting styles make for a fascinating match-up, with Nishikori's excellent backhand and solid defence countering Cilic's big serve and aggressive forehand.
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. The Croat will have taken great confidence from his win over Goffin and is fancied to come through in four or five sets.