The first European to see the area was Gabriel Moraga in 1806.

The county was named after the Estanislao River, which in turn was named in honor of Estanislao, a mission-educated renegade Native American chief who led a band of Native Americans in a series of battles against Mexican troops until finally being defeated by General Mariano Vallejo in 1826. Estanislao was his baptismal name, the Spanish name version after Saint Stanislaus the Martyr.

Between 1843 and 1846, when California was a province of independent Mexico, five Mexican land grants totaling 113,135 acres (458 km2; 177 sq mi) were granted in Stanislaus County. Rancho Orestimba y Las Garzas, Rancho Pescadero and Rancho Del Puerto were located on the west side of the San Joaquin River, and Rancho Del Rio Estanislao and Rancho Thompson were on the north side of the Stanislaus River. Additionally in 1844, Salomon Pico received a Mexican land grant of 58,000 acres (235 km2; 91 sq mi) in the San Joaquin Valley, somewhere near the Stanislaus River and the San Joaquin River in what is now Stanislaus County. However, the grant was never confirmed by the land commission.

Stanislaus County was formed from part of Tuolumne County in 1854. The county seat was first situated at Adamsville, then moved to Empire in November, La Grange in December, and Knights Ferry in 1862, and was ultimately fixed at the present location in Modesto in 1871.

As the price of housing has increased in the San Francisco Bay Area, many people who work in the southern reaches of the Bay Area have opted for the longer commute and moved to Stanislaus County for the relatively affordable housing.