The Escalante, Cottonwood, Little Dominguez and Big Dominguez Creeks cascade through sandstone canyon walls that drain the eastern Uncompahgre Plateau. Unaweep Canyon on the northern boundary of the NCA contains globally significant geological resources.

Nearly 30 miles (48 km) of the Gunnison River flow through the Dominguez-Escalante NCA, supporting fish, wildlife and recreational resources. The Old Spanish National Historic Trail, a 19th Century land trade route, also passes through it. A variety of wildlife call the area home, including desert bighorn sheep, mule deer, golden eagle, turkey, elk, mountain lion, black bear, and the collared lizard. There are 115 miles (185 km) of streams and rivers in the NCA, and there is habitat suitable for 52 protected species of animals and plants.