Sespe Creek's headwaters are in Portero Seco of the Sierra Madre Mountains, and are formed by more than thirty tributary streams in those and the Topatopa Mountains, before its confluence with the Santa Clara River, in Fillmore.
The Sespe Wilderness Area protects a portion of its watershed and channel.
Established in 1947, it is where the critically endangered species California condor (Gymnogyps californicus) has been re-introduced.
At least twelve native and introduced fishes can be found in the creek: A common fish in Sespe Creek is the threespine stickleback (Gasterosteus aculeatus), which is easily identified by its three dorsal spines.
The introduced species, green sunfish (Lepomis cyanellus), can be found in shallow, weedy areas.