Prospectors first located mineral resources in the area in the 1840s, including silver, gold, lead, zinc, and turquoise. Chloride was founded about 1863, but mining was not widespread until the 1870s after a treaty was signed with the Hualapai Indians. The town eventually grew to a peak of around 5000 inhabitants, and at one time Chloride was the county seat. By 1917 the population had fallen to 2000, and by 1944 it was nearly a ghost town.
In the 1960s the town was briefly a counterculture magnet, with Roy Purcell, a hippie artist, leaving behind the "Chloride Murals" outside of town.
Many of the yards along the main street have junk-art in their front yards.