The first human occupation of the Colorado Plateau probably began at least 12,000 years ago, near the end of the Pleistocene. These early occupants were most likely the big-game hunters of the Clovis and Folsum Paleo-Indian cultures. These hunters roamed the plateau in search of the mammoth and other large ice-age animals. By about 5500 B.C., people of the Archaic culture ranged over much of the Colorado Plateau, hunting small game and gathering various edible plants. The Archaic culture continued in the region for almost 6,000 years.

From about 1 A.D. until 1300 A.D., the Colorado Plateau was home to the Anasazi peoples. At the peak of their culture, the Anasazi may have numbered over a million in population. Separated from the southern reaches of the Colorado Plateau by the Canyonlands, a sub-culture, known as the Fremont culture developed in the northern Colorado Plateau. The Fremont occupied the Northern Colorado Plateau from about 500 A.D. to about 1250 A.D. The Fremont and Anasazi cultures are similar, but minor differences in artifacts and inferred customs suggest that they interacted rarely. At about 1300 A.D., the Anasazi culture collapsed. Remnants of the Anasazi-Fremont culture exist today as the Pueblo peoples: Hopi, Zuni, Laguna, and Acoma villages along the Rio Grande River.