Although little is known about the early prehistory of the area, most investigators assume that a sequence of human occupancy began prior to AD 1 and included desert archaic and basket maker cultures. For a period of several hundred years centered around 1100, both Kayenta and Fremont agricultural peoples occupied the area. The abandonment of a large Kayenta Anasazi village at Boulder in approximately 1275 ended the most significant period of prehistory. The village is presently part of Anasazi State Park. Hopi peoples apparently visited and hunted in the region for a period of 200 to 300 years. In the 1500's, Southern Paiutes began to visit the area and then occupied the region to historic times.

The Escalante River is generally considered to be the last major river to be "discovered" in the contiguous United States. In 1866 Captain James Andrus led a group of cavalrymen into the headwater benches of the Escalante River near the present community of Escalante. This is the first record of Anglo presence in the region. Members of the first and second Powell Expeditions did not find the mouth of the Escalante River when they passed through Glen Canyon in 1869 and 1871. The second Powell Expedition enlisted Jacob Hamblin of Kanab, Utah to re-supply the expedition at the mouth of the Dirty Devil River. Hamblin mistook the Escalante River for the Dirty Devil. Thus, in 1871 Hamblin became the first Anglo to travel through the Escalante River Canyon.