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In 1542 two ships flying the Spanish flag sailed the California coast under the command of Juan Rodriguez Cabrillo. Explorations continued with Sir Francis Drake in 1579 and Sebastian Vizcaino in 1603. In 1769, Spain sent expeditions to occupy California. Don Gaspar de Portola entered what is now San Luis Obispo County on September 2, 1769.

Father Serra founded the fifth California Mission at San Luis Obispo in 1772. San Miguel Mission was established in 1797. In 1822 California declared its independence from Spain. Mexico claimed California in 1825 and ceded it to the US in 1848, ending the Mexican-American War.

California became the 31st state in 1850, and San Luis Obispo became one of 27 original counties. 1861 brought stagecoaches traveling between San Francisco and Los Angeles. By 1886 the railroad reached as far south as San Miguel and Paso Robles. In 1894 the railroad, having surmounted the rugged Cuesta Ridge, finally reached San Luis Obispo.