Roddick, seeking his third tennis title in the nation's capital, beat seventh-seeded Croatian Ivo Karlovic 7-6 (9-7), 7-6 (7-5) in Saturday's semifinals.
Roddick, who is in his 36th career final berth, is going after his 23rd title overall. He missed last year's tournament due to an abdominal strain.
The 6-foot-9 Isner, playing in only his second-ever ATP event, was pushed to three tiebreakers before finally prevailing in nearly 2 1/2 hours against ninth-seeded Frenchman Gael Monfils 6-7 (4-7), 7-6 (7-1), 7-6 (7-2).
Isner, a 22-year-old from North Carolina, starred collegiately at the University of Georgia, which captured this year's NCAA championship with Isner as its top star. Isner headed to Washington ranked 416th in the world.