Paleo-Indian sites dating from c. 10,000 BC show that the San Bernardino county area has been inhabited for at least 12,000 years. Artifacts in the Calico area suggest much earlier human occupation, but this has not been confirmed. In the past three thousand years various Indian tribes flourished in the area: the Gabrielenos occupied the West Valley; the Serranos lived in the foothills of the San Bernardino Mountains; the Vanyumes lived along the Mojave River; the Mohave lived along the Colorado River; and in the 1500s the Chemehuevi moved into the Mojave Desert.

The first explorers to enter the area were Pedro Fages, Military Commander of California, in 1772 and Fr. Francisco Garces, a missionary priest, in 1774. On May 20, 1810, Franciscan missionary Francisco Dumatz, of the San Gabriel Mission, led his company into a valley. In observance of the feast day of St. Bernardine of Siena, Dumatz named the valley San Bernardino. This name was later given to the nearby mountain range, and later the city and county.

In 1842 the Lugo family was granted the Rancho San Bernardino, a holding of 37,700 acres encompassing the entire San Bernardino Valley. Captain Jefferson Hunt, of the Mormon Battalion, led a group of settlers into San Bernardino. In 1851 the Mormon Colony purchased the Rancho from the Lugos.

In 1860 gold was discovered in Holcomb and Bear Valleys in the San Bernardino Mountains, and placer mining began in Lytle Creek. Silver was being mined at Ivanpah in 1870, and the rich silver mines of the Calico district were developed in the 1880s. Borax was first discovered in 1862 in the Searles Dry Lake area near Trona, and transported out by twelve-, eighteen- or twenty-mule team wagons.

In 1857 three orange trees were set out on a farm in Old San Bernardino; by 1882 a rail car load of oranges and lemons grown in the East Valley was being shipped to Denver. As early as the 1840s vineyards were planted in the Cucamonga area and in the 1870 census San Bernardino County was credited with producing 48,720 gallons of wine.

In 1850 California was admitted into the United States. On April 26, 1853, San Bernardino County was created from parts of Los Angeles, San Diego and Mariposa Counties. In 1854 the city of San Bernardino was incorporated as the county seat. In 1893 Riverside County was created out of parts of San Bernardino and San Diego Counties.