Spain's Alamgro took the day's first match, scoring a quick 6-2, 6-1 decision over American wild card Rhyne Williams at River Oaks Country Club in Houston.
Almagro Sunday will go for his 13th career title -- all of which have come on clay courts.
He'll face the United States' Isner, who rallied to best defending champion Juan Monaco of Argentina 1-6, 6-4, 6-4.
Isner was the runner-up at last year's Houston event, falling in the final to Monaco.
He'll be looking for his sixth career title.