The Great River National Wildlife Refuge protects approximately 11,600 acres along 120 miles of the Mississippi River, stretching north of St. Louis, Missouri. Three separate units are located in the floodplain, on both the Illinois and Missouri sides of the river. The Clarence Cannon National Wildlife Refuge is also under the administration of the Great River Refuge. Great River Refuge, in turn, is part of the Mark Twain National Wildlife Refuge complex.

The Mississippi River corridor is one of the most important migratory bird corridors in North America. Because many habitats along the river have been lost or heavily degraded, refuge units are essential in providing links of high-quality habitat for many species of migratory birds, including shorebirds, songbirds, and waterfowl. As many as 70 to 80 percent of the ducks and geese migrating along this portion of the river are found on refuge units. In 1998, the Great River Refuge was designated as a globally important bird area. The refuge's proximity to St. Louis provides excellent educational opportunities to a large population.

The 1,700-acre Delair Division is protected from the river by a levee and includes marsh, open water, forest, and cropland. The Long Island Division is a 6,700-acre island complex in the river and contains some of the last remaining large contiguous stands of bottomland hardwoods in the area. This area is very important to migrant and resident bird species. The 2,100-acre Fox Island Division floods periodically and is important to waterfowl, numerous marsh and waterbirds, and songbirds.

The Mark Twain National Wildlife Refuge Complex includes Port Louisa, Two Rivers, Great River, Clarence Cannon, and Middle Mississippi River refuges. The complex headquarters is in Quincy, Illinois.

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