The refuge's primary purpose is to serve as a stopover for migrating ducks and geese. October thru December are the months of peak waterfowl use, with smaller concentrations of ducks and geese returning in March and early April.

Bald eagles follow the geese into the area, with many wintering here until March. Peak numbers of bald eagles usually occur in late November and December and again in early March. As many as 145 eagles have been seen here at one time. Bald eagles are often seen perched in cottonwoods along DeSoto Lake when waterfowl are present, and good viewing opportunities are available from the DeSoto Visitor Center. An interesting assortment of warblers, gulls, shorebirds and other bird life also can be observed on the refuge during the fall and spring migration.

In the summer, white-tailed deer and their fawns can be seen browsing in early morning and evening hours alongside refuge roads. Rabbits, raccoons, coyotes, opossums, and fox squirrels are also frequently observed along refuge roads and in fields. Backwater areas of DeSoto Lake and several wetlands on the refuge provide habitat for beavers, muskrats, and an occasional mink.

Woods, fields of native prairie grasses, and hedges along refuge roads attract a variety of songbirds and other wildlife, such as turkeys, pheasants and bobwhite quail. Red-headed woodpeckers abound along the woodland edge. In summer, wood ducks, perhaps the most beautiful of American waterfowl, are present in ponds throughout the refuge.