The creek begins on the east slope of Mount Wilson, inside the Angeles National Forest. It flows in a curve southeast through Santa Anita Canyon, then drops over the 60-foot (18 m) Sturtevant Falls. The North Fork comes in from the left about a quarter-mile above the falls, and the East Fork also from the left about a quarter-mile downstream. The creek then flows south through a group of about 80 historic cabins on the canyon floor, before receiving Winter Creek from the right near Chantry Flat. Shortly downstream of there, it drops over Hermit Falls and flows into Santa Anita Reservoir, which is impounded by the 225-foot (69 m) Santa Anita Dam.
Leaving the foothills the creek continues southwards through Sierra Madre, Monrovia and Arcadia as the Santa Anita Wash, flowing in a concrete channel. It turns southeast towards Azusa, then south again at Irwindale, where it empties into a small flood control basin.