The top-seeded Nishikori dispatched his Croatian opponent by a 6-4, 7-6 (7-0) margin, becoming the first player to win consecutive titles at the Memphis event since Tommy Haas in 2006-07.
Nishikori earned his fourth career ATP Tour crown.
Karlovic came up short in a bid for a sixth career championship and first since Bogota in 2013.
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