Settlement of Utah territory by whites began in 1847 and led to colonies in the region both north and south. In 1850 Mormon settlers were sent by Brigham Young to the Sevier River Valley. Native Americans in the area felt threatened when settlement encroached, and an altercation between settlers and Indians in 1852 left four Indians dead in Salina. At the same time, coming west through Salina Canyon on a railroad route survey was a government party led by John W. Gunnison. The surveyors were caught in an early morning ambush by vengeful Indians, who killed Gunnison and six of his crew.
Irrigation near the mouth of the river started with settlement in 1859 in west Millard County. Obtaining water for irrigation was the most significant challenge for settlers in the semi-arid land. Uncontrolled flooding caused downstream irrigators to abandon many dams before they were finally permanently established in 1912.