The Middle Mississippi River National Wildlife Refuge was established on May 31, 2000 and is part of the Mark Twain National Wildlife Refuge Complex. The complex was established in 1958 for the protection of migratory birds and spans 350 miles along the Mississippi River in the states of Iowa, Illinois, and Missouri. The Middle Mississippi River Refuge has three divisions - Meissner Island, near Valmeyer, Illinois; Harlow Island, near Festus, Missouri; and Wilkinson Island, near Gorham, Illinois.

Refuge lands were purchased in response to the great flood of 1993 and are unique in the refuge complex. The refuge tracts lie within the uncontrolled portion of the Middle Mississippi River, below the confluence with the Missouri, where river levels are not regulated by the lock and dam system. Water levels may fluctuate greatly in this open river section of the Mississippi, and frequent flooding occurs on these lands. Many of these areas had previously been cut off from the floodplain by private levees that protected acgricultural lands. Most of the levees were breached by the 1993 flood and will not be repaired. These lands will provide access to the floodplain for native fish during high water stages and create a corridor of floodplain forest habitat for migratory birds and resident wildlife.

The Mark Twain National Wildlife Refuge Complex includes Port Louisa, Two Rivers, Great River, Clarence Cannon, and Middle Mississippi River refuges. The refuge headquarters for Middle Mississippi Refuge is co-located with Crab Orchard National Wildlife Refuge.

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