The Santa Margarita de Cortona Asistencia was established in 1787 as an asistencia ("sub-mission") to Mission San Luis Obispo de Tolosa, then in the Spanish Las Californias Province. Its site is near the present-day city of Santa Margarita, in San Luis Obispo County, central California.

Santa Margarita is a town and census-designated place located in San Luis Obispo County, California. It was founded in 1889 near Cuesta Peak and San Luis Obispo along State Route 58. The town's name comes from the Mexican Alta California land grant of Rancho Santa Margarita. It is home to the Santa Margarita de Cortona Asistencia site. The population was 1,259 at the 2010 census.