Siskiyou County was created on March 22, 1852, from parts of Shasta and Klamath Counties, and named after the Siskiyou mountain range. Parts of the county's territory were given to Modoc County in 1855.

The origin of the word Siskiyou is uncertain. It may be derived from the Chinook word for a bob-tailed horse or from the French phrase six cailloux (six stones in English).

In 2010, the population of the county was 44,900. Only one town, Yreka, has a population greater than 5,000.

1941, Gilbert Gable, the mayor of Port Orford, Oregon, proposed that the counties of northern California and southern Oregon secede from their respective states and form a new state, the State of Jefferson. Gale felt that the region was too from the state capitals in Salem (Oregon) and Sacramento (Califonia) and was poorly understood and served by legislators and bureaucrats.

The secessionist notion survived over the years, sometimes in jest, sometimes in earnest.

In the late 1990s, the Klamath water war galvanized local property-rights proponents. The now-legendary conflict fueled residents’ feeling that the region was a place apart, misrepresented by urban lawmakers who threatened a way of life with their environmental regulations and bureaucratic ineptitude. [High County News, 13 November 2006]

The State of Jefferson, at its most ambitious, includes twelve California counties (Butte, Del Norte, Humboldt, Glenn, Lassen, Mendocino, Modoc, Plumas, Shasta, Siskiyou, Tehama and Trinity) and seven Oregon counties (Coos, Curry, Douglas, Jackson, Josephine, Klamath and Lake).

Siskiyou County has always been the heart of the State of Jefferson. On September 3, 2013, the County Board of Supervisors voted four to one in favor of secession from California.