The Santa Ana Mountains form the drainage divide with San Juan Creek on the northwest side of the San Mateo Creek valley, and the Santa Margarita Mountains on the southeast separate San Mateo Creek from the Arroyo San Onofre, a creek that drains westwards to the Pacific Ocean. Arroyo San Onofre is also the closest major stream to San Mateo Creek by location of the mouth. The next closest is Segunda Deshecha Cañada, further north. Much of the upper San Mateo Creek watershed is encompassed by the central Cleveland National Forest and the lower lies mostly within Camp Pendleton. The closest city is San Clemente, northwest of the creek's mouth.