The river is 57.4 miles (92.4 km) long[6] and originates on the north slopes of Big Pine Mountain,[7] at approximately 6,320 feet (1,930 m).

The first half of the river, in the Los Padres National Forest, specifically the San Rafael Wilderness, travels roughly northwest.

This makes the Sisquoc River, which remains undammed, an important stream for surviving southern steelhead populations.

[10] One tributary, Horse Creek (Horse Canyon), was dammed in 1968 and the 4.5 foot high, 60 foot wide dam eventually created a scour pool, increasing the drop to over 8 feet and creating an impassable barrier to spawning steelhead.

[11] The discovery of a male adult California Golden beaver (Castor canadensis subauratus) specimen collected as "wild caught" in 1906 "along the Sespe River in Ventura County" is physical evidence that Golden beaver were historically extant in coastal streams in southern California.