Cilic's mental fragility proved to be his Achilles' heel once more as he squandered several opportunities against Alexander Zverev on Monday before losing 6-7, 6-7.
The Croat served for the first set and also went a break up in the second but he couldn't maintain his form and composure in the key moments and that has been a recurring problem in recent years.
Cilic has won seven of his previous ten meetings with Isner and leads four to two on hard courts and that will give him some belief that he can emerge victorious from this match-up and get some points on the boards.
Isner did not play particularly badly in his opening match against Novak Djokovic but there was little he could do against the world number one who managed to nullify the American's serve.
He did not seem overwhelmed by the occasion and he seems to be relishing the event after having been a late replacement for the injured Rafael Nadal, although he will want to improve on his return game statistics as he made little dent in Djokovic's serve.
The omens are good for Isner when taking a deeper look at his head-to-head record with Cilic; the American has won three of their last four matches, has won their only meeting on an indoor hard court, and beat Cilic in the one match they have played in 2018.
Two big servers face off here in a match that is vital to the pair's qualification hopes after opening match defeats. Cilic will probably feel he should have beaten Zverev on Sunday but his inability to convert chances in important moments plagued him yet again and it will be interesting to see how he responds here.
Isner appeared to have no answers to Djokovic's brilliance in his own opener but he should have more opportunities here against a fragile Cilic. The American has had the upper hand in recent meetings and, if he can improve his return game, he can edge a tight match. Isner in three sets.