Roddick defeated the 22-year old Isner, who starred at the University of Georgia, 6-4, 7-6 (7-4).
Roddick captured his 23rd career title in his 36th final. He's now won 10 straight matches at this event after missing last year's tournament due to an abdominal strain.
Roddick, the 2006 U.S. Open runner-up, also won in 2001 and 2005.
The 6-foot-9 Isner, who led the Bulldogs to the NCAA title last year, was playing in just his second-ever ATP event and was ranked 416th in the world.