Mono County was formed in 1861 from parts of Calaveras County, Fresno County and Mariposa County. Parts of the county's territory were given to Inyo County in 1866.

The county is named after Mono Lake which, in 1852, was named for a Native American Paiute tribe that inhabited the Sierra Nevada from north of Mono Lake to Owens Lake. The tribe's western neighbors, the Yokuts, called them monachie meaning "fly people" because the pupae of a fly was their chief food staple and trading article.