European settlement in what is now San Diego County began with the founding of the Mission San Diego de Alcala by the Spanish, in 1769.

San Diego County was one of the original counties of California, and was created at the time of statehood in 1850. It was named after San Diego Bay, which had been rechristened in 1602 by Sebastián Vizcaíno in honor of the Franciscan St. Didacus of Alcalá, known in Spanish as San Diego de Alcalá de Henares, and whose name was borne by Vizcaíno's flagship.

Parts of the county were later divided off to create Riverside County, in 1893, and Imperial County, in 1907.