Seedskadee NWR was established in 1965 as mitigation for the loss of habitats when Flaming Gorge and Fontenelle dams were constructed. The riparian corridor is an important migration route and nesting area for a wide variety of migratory waterfowl and passerine bird species. Trumpeter swans, bald and golden eagles, Wilson's warblers, mountain bluebirds, and sage grouse are a few of the more commonly observed species of the Refuge's 220 documented bird species. The Refuge also provides habitat for a variety of mammals including moose, mule deer, pronghorn antelope, porcupine, bobcat, beaver, coyote, badger, and white-tailed prairie dogs.

Fishery resources are managed cooperatively with the Wyoming Game and Fish Department. As a special regulation area, the river supports catch and release fishing for trophy brown, cutthroat, and rainbow trout.

Refuge lands are rich in historic and cultural resources due to the fact that the area was used by nomadic Indian tribes, fur trappers, and early pioneers. Many of the old campsites, river crossings, trails (Oregon, Mormon, California), and early structures can still be located on the refuge.

Approximately 10,000 people visit the Refuge annually and more than 20 educational and civic organizations participate in environmental education or volunteer programs.