Tuilla, as it was originally spelled, was one of six counties created in January 1850. Its boundaries were changed a number of times before it achieved its present size as the state's second largest county.

The Mormons herded livestock in Tooele Valley before permanent settlement began in 1849. The early settlers farmed, built gristmills and sawmills, and manufactured salt, charcoal, lime, adobe bricks, and woolen products. Large sheep and cattle herds were developed, and hay and grain became important crops. But mining and smelting, not agriculture, led the county's growth from the 1860s to World War II.

The Rush Valley Mining District, organized in 1864 by soldiers from Fort Douglas, included all of the western Oquirrhs. More than 500 mining claims were located during the first year. Of the mining towns founded in Tooele County, Ophir and Mercur became the most important. Ophir boomed in the 1870s with an estimated population of 6,000 and mines that produced millions of dollars in silver, lead, zinc, and gold. Mercur endured several boom and bust cycles as well as two major fires; with a population estimated as high as 10,000 it flirted briefly with the idea of taking the county seat from Tooele City.