River modifications have had detrimental effects on biota that depend on river systems; therefore, information is needed to understand these effects and direct management efforts. Channel catfish (Ictalurus punctatus) are important recreationally, commercially, and ecologically in the Middle Mississippi River (MMR), but few studies have examined their habitat requirements, and food habits have not been evaluated in the MMR. Information about habitat use and food habits could help direct management efforts for channel catfish. To more thoroughly understand the synergistic relation between channel catfish and the associated habitat, we used data from the United States Army Corps of Engineer’s Long-Term Resource Monitoring Program to evaluate channel catfish use of large-scale river features (i.e., macrohabitats) and more fine scale mesohabitats (i.e., substrate type, depth, and velocity). Stomach contents from channel catfish were identified and quantified to determine the relative importance of specific prey items in diets. Channel catfish presence was positively affected by current but negatively affected by depth. Off-channel habitats appeared more suitable for channel catfish. In terms of food habits, Cambaridae, fish, and vegetation were most frequently found in the diet, but a variety of other food items were consumed. Conserving premodification habitat characteristics, such as open side channels, shallow sandbars, and seasonally inundated floodplains, as well as habitats with high forage productivity, should help to sustain a stable population of channel catfish in the MMR. Future studies could examine the tenets of the optimal foraging theory within these habitats to determine the mechanisms regulating channel catfish habitat use and prey selection.