The area was first settled by the Chumash Native Americans around 10,000 years ago. As the Alta California (Upper California) coast was settled by Spanish Franciscan missionaries in the late 18th century, the El Camino Real (the Royal Road or King's Highway), a road from Loreto, Baja California, Mexico to Sonoma, California, and connecting the Spanish missions in California, was established through the heart of what would later be known as Agoura Hills.
In about 1800, Miguel Ortega was granted a Spanish grazing concession called Rancho Las Virgenes or El Rancho de Nuestra Señora La Reina de Las Virgenes. The grant was abandoned after Ortega's death in 1810, and José Maria Dominguez was given Rancho Las Virgenes as a Mexican land grant in 1834. Maria Antonia Machado de Reyes purchased the rancho from Dominguez in 1845. (The "Reyes Adobe" ranch headquarters sits today in central Agoura Hills, where it is part of the Reyes Adobe Museum built around 2004 and owned by the Los Angeles County Parks and Recreation Department.)
By 1900, Agoura Hills was being used as a popular stage stop for travelers along the Camino Real because of its natural spring at the foothills of Ladyface Mountain, one of Agoura Hills' defining geographic features.
In the 1920s, the community was briefly known as Picture City, as Paramount Pictures owned a ranch known as Westerns. To obtain a post office of their own, the residents were required to choose a one-word name, and in 1927 chose the shortest name proposed: a misspelling of the last name of Pierre Agoure, a local Basque man and French immigrant who had settled in the area in 1871 to live the lifestyle of the Mexican rancher. Styling himself Don Pierre Agoure, he was a successful sheep herder and had a reputation as a swashbuckler.
Agoura Hills began to grow in the late 1960s after the Ventura Freeway section of U.S. Route 101 was built through the city's heart, isolating its northern half from its south. The first housing tracts in Agoura were Hillrise, Liberty Canyon and Lake Lindero. Rapid growth continued during the 1970s, when schools were built and much of downtown erected.