After Mormon missionaries established a way station between Utah and California at Las Vegas in 1855, they received a directive from the Church of Jesus Christ of Latter-day Saints to scout more town sites just north of the area along the Muddy River. Not everyone approved, but Church officials authorized new Muddy settlements anyway. Before long, the Muddy missionaries discovered why no one else had settled there before them.

Europeans discovered the Muddy River Valley when Spaniards in New Mexico began searching for a route to California. Spanish explorers sought a more northern trail when they concluded that Native Americans in Arizona were hostile. As desert stretched far and wide along this path, the confluence of the Muddy and Virgin Rivers northeast of Las Vegas appeared as an oasis for the weary travelers.

Various EuroAmerican parties also noted this alluring watering site as they moved through Southern Nevada in the early nineteenth century. Traders, trappers, and government scouts all paused along the Muddy River's welcoming banks to rejuvenate before venturing on into the parched wilderness. But not until Mormon settlers arrived in the 1850s did anyone seriously consider settling the area because the Vegas and Muddy Valleys were inundated with salts.

A number of factors lay behind the Latter-day Saints' decision. First was their general goal of achieving localized, economic self-sufficiency. Having fled from persecution in the Midwest, Mormon leaders hoped to completely cut ties with the gentile—as Mormons called non-Mormons—world. Yet when they discovered that the Salt Lake Valley was too arid to provide enough food and raw materials for a large and growing population, Church officials began looking to expand into the wider Great Basin, and south into the Mohave Desert.

To accomplish this, Church President Brigham Young established Mormon colonies across diverse ecological zones. Settlers in each area produced one or two resources and deposited surpluses in the form of tithing in central repositories, to be distributed as needed—for example, Cedar City, Utah, was the "iron mission," providing that ore to other Mormon communities. Mormon leaders viewed the Muddy River Valley as an ideal spot for growing and then sharing warm-climate crops.

Over time, Mormon leaders realized they would have to import some goods, at least for the short term. This, then, became the second factor driving them to settle the Muddy River Valley. It was an ideal resting spot for travelers hauling in merchandise, and the confluence with the Virgin River connected the Muddy to a port site selected to receive commodities brought up the Colorado River by steamboat.

Mormons arrived at the Muddy in January 1865 and established St. Thomas; six months later a second group founded St. Joseph nine miles to the north. Both discovered ample evidence that local Paiutes were growing crops along the Muddy River, yet the settlers saw nothing wrong with expropriating the Native Americans' property. It was the Paiute practice to plant corn, beans, squash, and wheat before migrating to the cooler uplands for gathering and hunting. They returned every fall to harvest surviving crops. Needless to say, their 1865 return was an unhappy one.

Not surprisingly, "Indian troubles" soon became a problem for the Muddy Valley settlements. Anger over losing their farm land as well as their belief in sharing resources prompted some Paiutes to appropriate Mormon animals and foodstuffs. Unwilling to admit they had pushed members of the tribe into food destitution, the Mormons called the Paiutes' behavior "theft" and "beggary," often responding by punishing "offenders." The Paiutes sometimes reciprocated with violence.

In addition to difficulties with Native Americans, the Muddy Valley Mormons faced severe environmental and climatic conditions. As the Muddy's source was a mineral spring, it was salty and unsuitable for large-scale irrigation agriculture. Searing heat in the summer and frequent bouts of drought tested the settlers. Man-made disasters also posed challenges. On August 18, 1868, the second St. Joseph burned down after two young boys lost control of a fire while roasting potatoes.

Many Mormon families simply could not endure the Muddy Mission's extreme hardships and left. To determine whether the settlements could survive, Brigham Young visited in March 1870. He was not hopeful. That fall, a flood wiped out the new Muddy village of West Point.

The final straw, however, came during a fight over taxes. In 1870, a new boundary survey confirmed that the Muddy settlements were in Nevada, not in Utah or Arizona. Both of those territories had accepted taxes in the form of goods, but Nevada officials wanted back taxes paid in gold or silver. Few settlers could afford this, so in early 1871 all but one Mormon family left the Muddy Mission for good. The community remained largely abandoned, and in the early 1930s the Boulder Canyon Project led to the creation of Lake Mead, which washed over the Muddy Mission.