Isner downed Almagro 6-3, 7-5 to take his first career clay-court victory, defeating the longtime specialist on the surface.
The fifth-seeded Isner needed 1 hour, 21 minutes to notch the triumph at River Oaks Country Club.
He was the runner-up at last year's Houston event to Argentina's Juan Monaco, whom he beat in Saturday's semifinals.
Almagro was seeking his 13th career victory on clay.
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