Isner had beaten his compatriot Andy Roddick, who was the top seed, in the semi-finals, and followed that up by edging Frenchman Julien Benneteau over three sets in the final.
The 26-year-old fourth seed, very much at home at the tournament in North Carolina, the state where he was born and raised, dropped the first set against Benneteau who made the most of a break of serve in the ninth game.
That was the last time Isner's booming serve was broken though, as he clinched a 4-6 6-3 6-4 victory at the Forest Wake University venue, for his second title of the year. The first came on grass at Newport, Rhode Island, in the week following Wimbledon.
The American number three and world number 28, who served 19 aces against Benneteau, now heads to New York for a tough first-round match against Marcos Baghdatis of Cyprus at Flushing Meadows.
Benneteau will take on Spain's 10th seed Nicolas Almagro at the year's final grand slam, which is due to begin on Monday.