Early explorers of the Big Muddy were impressed with the diversity of wildlife found along the river. Lewis and Clark and their Corps of Discovery documented previously unknown species of plants and animals. Lewis, at a location now part of the Big Muddy NFWR, first formally described the Eastern Wood Rat. The river soon became a primary transportation corridor for the westward migration of our growing country. Small towns sprang up along the river and farms were hacked out of the floodplain forests, but the river did not give up her resources easily as floods and river hazards sank many a pioneer's dreams.

At the end of the 19th century, Congress appropriated funds for the improvement of navigation on the Missouri River. These improvements started with snag removal but grew into steps to alter the river's course in order to provide a permanent channel for navigation. By the 1950s, the river had been converted into a narrow and swift channel for the benefit of navigation. Sediment loads were reduced to less than half of previous amounts due to construction by the US Army Corps of Engineers of large reservoirs on the Missouri River in the Dakotas and Montana. The changes greatly reduced important habitat types and were detrimental to many river-dependent species of fish and wildlife.

Although channeled with piling and rock navigation structures, lined with massive earthen levees and armored with millions of tons of rock, the river has never been totally controlled. Massive floods have taken their toll in towns, cities and farms in the fertile Missouri River floodplain. The devastating flood of 1993 was a harbinger of change. At a time when numerous landowners wanted to move their farming operations to higher, more secure locations, fish and wildlife professionals put forth plans to restore some of the fish and wildlife habitat along the Missouri River that had been lost to navigation, bank stabilization and flood control projects in previous decades.

The Big Muddy National Fish and Wildlife Refuge was authorized on September 9, 1994, "for the development, advancement, management, conservation, and protection of fish and wildlife resources." Numerous farms heavily damaged by flooding were purchased for the refuge to be restored as fish and wildlife habitat. The refuge has grown to over 11,000 acres and is approved to acquire a total of 60,000 acres of floodplain lands on the lower Missouri River between Kansas City and St. Louis Missouri.