The river rises in southern Siskiyou County on the edge of the Shasta-Trinity National Forest, approximately 10 miles (16 km) southwest of Weed.

Pluto's Cave is an example of voids remaining after highly fluid lava drained from underground conduits which were fed by volcanic vents to the east.

Bypassing Big Springs 30 miles (48 km) from the mouth, the river picks up more agricultural runoff as it meanders north between irrigated fields.

The river then passes between Yreka and Montague, 10 miles (16 km) from the mouth, crossed by California State Route 3 and Interstate 5 for the final time.

It then enters a canyon in the Klamath Mountains, 3 miles (4.8 km) from the mouth, and begins to parallel California State Route 263.