The name Seedskadee is derived from the Shoshone language word sisk-a-dee-agie, which means "river of the prairie hen".

The area was first visited by white explorers in 1811 and was later a crossroads for the Oregon and Mormon Trails; many of the original wagon tracks left by early pioneers can still be seen.

The refuge includes 36 miles (56 km) of the Green River, which is a water source for shrubs and cottonwoods in an otherwise arid region.

Trumpeter swans, bald eagles, sage grouse, and numerous species of ducks can be found.

Dozens of species of mammals including coyote, porcupine, pronghorn, mule deer, bobcat, and moose are indigenous to the region and are protected under law.