The first attempt to settle Moab Valley came in 1855, with the establishment of a mission in the Elk Mountains (now the La Sals). The following spring the LDS Church "called" 41 men to man the mission. The company reached the Colorado River in mid-June. By mid-July the men had planted crops and built a stone fort. They held friendly meetings with the Indians, converted and baptized some of them. During late September, in a sudden series of attacks, Indians killed three of the Mormons and set fire to haystacks and log fences. The missionaries abandoned the fort the next morning without eating breakfast. They departed so quickly that water was left running in the irrigation canal from Mill Creek. Water continued to run through this ditch, year after year, until eventually it carved an arroyo 25 feet deep.

The next settlers were probably 2 brothers, George and Silas Green, who brought 400 cattle into the valley about 1875. They were apparently killed by Indians. In the summer of 1877 two prospectors, William "Nigger Bill Granstaff, a mulatto, and a French-Canadian known only as "Frenchie" took possession of the fort, and laid claim to the valley. In 1878 A.G. Wilson made a trade with "Frenchie" for his land, but when he returned with his family the following spring the Frenchman had traded the same land to Walter Moore, and had left the valley. The mulatto, however, remained until 1881. In that year the settlers had their last trouble with Indians. A band of Paiutes and Navajos from Colorado came into the La Sal Mountains, killing and plundering settlers who grazed their cattle there. After a running fight in which ten whites and 27 Indians were killed, the Indians were driven back to their reservation. During this trouble "Nigger Bill", accused of selling whisky to the Indians, fled into Colorado by way of Nigger Bill Canyon (now referred to as Negro Bill Canyon).

A post office was established, and a committee chose the name Moab for the town. The original Moab was a biblical kingdom at the edge of Zion. Grand County was created in 1890, and Moab was named the county seat. The population of the county in 1940 was approximately 2,000, most of whom derived their livelihood from sheep and cattle.

Oil exploration in the 1920s caused some excitement, but nothing like that of the uranium boom that began in 1952. Moab's population tripled in just 3 years as eager prospectors swarmed into the nearby canyons. One of these hopefuls, Charlie Steen, did hit it big. Experts had laughed at Charlie's efforts until he discovered the Mi Vida uranium bonanza about 30 miles south of town. An instant millionaire, he built a large mansion overlooking Moab and hosted lavish parties attended by Hollywood celebrities.