Tuolumne County was one of the original counties of California, created in 1850 at the time of statehood. Prior to statehood, it had been referred to as Oro County. Parts of the county were given to Stanislaus County in 1854 and to Alpine County in 1864.

The name Tuolumne is of Native American origin and has been given different meanings, such as Many Stone Houses, The Land of Mountain Lions and, Straight Up Steep, the later an interpretation of William Fuller, a native Chief. Mariano Vallejo, in his report to the first California State Legislature, said that the word is "a corruption of the Indian word talmalamne which signifies 'cluster of stone wigwams.'" The name may mean "people who dwell in stone houses," i.e., in caves.