Named after Major General Joseph Wheeler, it was established to provide a habitat for wintering and migrating birds in the Eastern United States.

By 1936, the Tennessee River was impounded for flood control with the nearby Wheeler Dam providing hydroelectric power.

In 1938, the refuge was established by executive order of President Franklin D. Roosevelt and became the first NWR to be overlain on a multipurpose reservoir.

This food source allows the refuge to be the home of Alabama's largest duck population and its only significant concentration of wintering Canada geese.

About 10 endangered species live on the refuge; also a small population of American alligators are present within the reserve; they were reintroduced into the area following historical extirpation from northern Alabama.

Wheeler NWR offers five hiking trails ranging in length from 200 yd (180 m) to 4 mi (6 km), providing opportunities to view wildlife in a wide variety of habitats.

The Tennessee River provides excellent fishing opportunities for bass, sunfish, crappie, sauger, and catfish.