The Cuyama River's source is in San Emigdio Mountains, within the Chumash Wilderness area of the Los Padres National Forest at an altitude above . The river's upper reaches are in Ventura County, where several tributaries join before the mainstem river exits Los Padres National Forest. After leaving the national forest the river enters Santa Barbara County and flows through the Cuyama Valley, which lies between the Caliente Range and the Sierra Madre Mountains. The river flows past the towns of Cuyama and New Cuyama. Through most of the Cuyama Valley and downriver to its confluence with the Sisquoc River the Cuyama River forms the approximate boundary between Santa Barbara County and San Luis Obispo County.