The valley where Moorpark is located was originally inhabited by the Chumash. The area was part of the large Rancho Simi land grantgiven in 1795 to the Pico brothers (Javier, Patricio, and Miguel) by Governor Diego de Borica of Alta California.

Robert W. Poindexter, the secretary of the Simi Land Company, received the land that made up the original townsite of Moorpark when the association was disbanded in 1887. Moorpark was founded in 1900 when the application for a post office was submitted. The application lists that there was already a railroad depot in the town. The town grew after the 1904 completion of a 7,369-foot (2,246 m) tunnel through the Santa Susana Mountains, which allowed theSouthern Pacific Railroad to establish a depot there, a depot which lasted until 1965.