DeSoto National Wildlife Refuge's primary wildlife management role is to serve as a stopover for migrating ducks and geese during their fall migration between the Arctic nesting grounds and the Gulf Coast wintering areas. During typical years, a half million snow geese utilize the refuge as a resting and feeding area and populations of 75,000 or more ducks, mostly mallards, are common on the refuge. November is the month of peak waterfowl use, with less spectacular concentrations of ducks and geese returning in March and early April.

Bald eagles follow geese into the area, with many eagles 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 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 fall (Sept-Oct) and spring (Mar-May) migrations.

In the summer, white-tailed deer, with one or two fawns, are often seen in the morning and evening hours beside refuge roads. Wild turkeys gather in large groups along the roads and in the fields to strut. Cottontail rabbits, raccoons, coyotes, opossums, and fox squirrels also are frequently observed along refuge roads. Backwater areas of DeSoto Lake and several wetlands on the refuge serve as habitat for herons, beaver, muskrat and an occasional mink. Grassland birds are attracted to areas of restored prairie for nesting.

Woodland edges, fields of native prairie grasses and wildflowers near refuge roads attract a variety of songbirds and other wildlife such as pheasants and bobwhite quail. Red-headed woodpeckers abound along the woodland edge. Wood ducks, perhaps the most beautiful of America's waterfowl, may be seen in ponds throughout the refuge.