In the early 1900s, the Elsberry Drainage District built levees and ditched the area. A pumphouse was constructed in the 1920s in order to grow rice, however, the effort lasted only until 1931, when prices plummeted due to the Great Depression.

By 1964, all the land, excluding timbered areas and deep pools of water along the east portion of the refuge, was farmed. Clarence Cannon National Wildlife Refuge was purchased in fee title on August 11, 1964, with funds in part from the sale of migratory waterfowl stamps. The refuge, named after Congressman Clarence Cannon, was established to provide a feeding and resting area for migratory birds. Management emphasis has moved away from cropland and now focuses on wetland management, which benefits a wide variety of wildlife.