Third-seeded Monaco cruised past American qualifier Robby Ginepri 6-1 6-0 in just 56 minutes, never facing break point, while Isner booked his place in the semi-finals with a 6-3 3-6 6-3 victory over Ricardas Berankis.
The big-serving Isner produced 19 aces and won 89 per cent of his first serve points as he overpowered the Lithuanian.
In other semi-final, top seed Nicolas Almagro will face 22-year-old American Rhyne Williams after Spaniard Almagro defeated Italian Paolo Lorenzi 6-4 6-4.
Almagro is seeking his 13th career title on his Houston debut. All of his previous 12 wins also been on clay.
Williams beat Spaniard Ruben Ramirez Hidalgo 7-6 1-6 6-4.
US Clay Court Championship results
3-Juan Monaco (Argentina) beat Robby Ginepri (U.S.) 6-1 6-0
5-John Isner (U.S.) beat Ricardas Berankis (Lithuania) 6-3 3-6 6-3
1-Nicolas Almagro (Spain) beat 7-Paolo Lorenzi (Italy) 6-4 6-4
Rhyne Williams (U.S.) beat Ruben Ramirez Hidalgo (Spain) 7-6(1) 1-6 6-4