Roddick will play for his 32nd ATP World Tour title on Sunday against Luxembourg's Gilles Muller, who knocked off No. 8 Go Soeda of Japan 6-4, 6-3.
Isner was attempting to win his second straight event for the first time in his seven-year career, but fell short in Atlanta for the third straight year.
He lost to Mardy Fish in the past two Atlanta finals.
Roddick will team up with Isner as U.S. doubles partners when the Olympics begin next week at Wimbledon.