The river begins at Lake Chapala, running through Ocotlán and continuing roughly north-west through the Sierra Madre Occidental range, receiving the Verde, Juchipila, Bolaños, Huaynamota, Mololoa, and other tributaries.

Downstream from Lake Chapala, the river and its major tributaries have carved deep narrow canyons, or barrancas, which can be 600 meters lower than the surrounding plateau.

The lower elevation and year-round moisture in the canyon bottoms sustain forests, which include many coastal tropical species not found on the plateaus.

From Aguamilpa, the river descends to the coastal lowlands, passing by Santiago Ixcuintla and empties into the Pacific Ocean, 16 km (10 mi) northwest of San Blas, in Nayarit.

According to an article named Water use (and abuse) and its effects on the crater-lakes of Valle de Santiago, Mexico “most Mexican lakes are in an advanced state of desiccation or senescence, with volume and surface area greatly reduced because of human activities”.

The Instituto Mexicano de Tecnología del Agua (IMTA) found over a thousand different chemicals in the main channel and its tributaries.