In 1776 the Dominguez-Escalante expedition crossed the county from north to south at the eastern end, passing near present Nephi. Jedediah Smith traversed the western end of the county in 1826 and via Fish Springs in 1827. In 1843-44 John C. Frémont journeyed through the county's eastern end en route north. Government explorers John W. Gunnison and J.H. Simpson traveled in the area in 1853 and 1859, respectively. Gunnison touched the extreme southeast portion of the county while Simpson pioneered the route later used by the Pony Express and the transcontinental telegraph.

In 1852 the legislative assembly created Juab County, which extended as a narrow strip to what was then the western boundary of Utah Territory (now the western boundary of Nevada). The western portion was removed in 1854 to form part of Summit County, Nevada, and several other changes in Juab's borders have been made over the years.

The first settlement in Juab Valley occurred in 1851 when a group of Mormon settlers arrived near Salt Creek, at present-day Nephi. Their economy was based primarily on agriculture.