The creek drains an area of about 497 square miles (1,290 km2), making it the Santa Clara River's biggest tributary in terms of watershed size.

[5][6] The Smith Fork of Piru Creek, with headwaters in the San Emigdio Mountains, comes in from the left about 5 miles (8.0 km) south of Gorman.

[5][6] Thousands of years ago, Native Americans of the Chumash group lived in the area, but by 500 CE, their former territory along Piru Creek had been occupied by the Tataviam.

[10] In 1842, traces of gold were found on a nearby tributary of the Santa Clara River, Placerita Creek, drawing prospectors to the area.

[9] By the late 19th century, prospectors had discovered traces of calcite on Piru Creek in Lockwood Valley near Frazier Mountain, north of present-day Pyramid Lake.

[12] Hiking, camping, off-roading and rock climbing are some of the recreational opportunities in the Los Padres National Forest that surrounds much of the Piru's course.

[19] From 0.5 miles (0.80 km) downstream of Pyramid Dam to the Los Angeles-Ventura County line, Piru Creek in various sections is designated a National Wild and Scenic River.

In the present day, the uppermost limit of natural fish spawning in the creek is below Pyramid Dam, where a cement culvert adjoining the remains of Highway 99 creates a 15-foot (4.6 m) waterfall.

Piru Creek was once a popular spot for both fly fishing and bait-casting anglers as it contained both wild and hatchery-raised rainbow trout, along with largemouth bass.