The Tongva and Juaneño/Luiseño Indians inhabited Orange County long before the Spanish arrived in 1769. In 1776, Spanish priest Fray Junipero Serra founded Mission San Juan Capistrano here, naming the area Vallejo de Santa Ana (Valley of Saint Anne). Mexico gained independence from Spain in 1822, and by the mid-1830s the Spanish mission era was over.

Cattle ranching became the area's biggest industry until a severe drought in the 1860s. In 1887, silver was discovered in the Santa Ana Mountains, attracting so many new settlers that the California legislature decided in 1889 to divide Los Angeles County into two counties. Newly-formed Orange County was named for its most famous product, but other agricultural crops (especially avocados) were also important.

In 1904, the Pacific Electric Railway connected Newport Beach and Santa Ana to Los Angeles, and early Hollywood celebrities soon discovered the county as a weekend retreat destination.

Standard Oil discovered oil in Huntington Beach in 1920, creating California's fourth-largest oil field. The boom lasted into the 1930s. Agriculture continued to be an important part of the Orange County economy until World War II. After the war, returning servicemen who trained here came back to Orange County to settle, and the area became a bedroom community for the metropolitan area's burgeoning manufacturing industries. In 1955, Disneyland opened in Anaheim, propelling Orange County's reputation as a vacation destination. By the 1980s, Orange County became California's second-largest county.