Mendocino County was one of the original counties of California, created in 1850 at the time of statehood. Due to an initially minor white American population, it did not have a separate government until 1859 and was under the administration of Sonoma County prior to that. Some of the county’s land was given to Sonoma County between 1850 and 1860.

The county derives its name from Cape Mendocino (most of which is actually located in adjacent Humboldt County), which was probably named in honor of either Antonio de Mendoza, Viceroy of New Spain, 1535–1542 (who sent the Juan Rodríguez Cabrillo Expedition to this coast in 1542), or Lorenzo Suárez de Mendoza, Viceroy from 1580 to 1583. Mendocino is the adjectival form of the family name of Mendoza.