Geoarchaeological cores from an infilling channel within the meander belt of the Central Mississippi Valley recovered multiproxy evidence of vegetation changes during the Late Holocene. The sampling site, Wapanocca Bayou (Crittenden County, Arkansas), is flanked by levees that supported settlements of prehistoric Late Woodland and Mississippian farm sites, villages, and towns (AD 300–1650). These settlements include the Bradley site (3CT7), which was potentially the capital of a powerful Native American chiefdom visited by Hernando De Soto's North American expedition in 1541. Age-depth modeling of radiocarbon dates from a 10+ meter core indicates continuous infilling of the channel since at least 2,450 cal BP. Palynological records preserve diachronic and patterned shifts in vegetation reflecting significant disturbances in these dynamic meander-belt settings. Coeval trends in soil phosphorus, organic matter, charcoal concentrations, and magnetic susceptibility combined with archaeological evidence for increasingly intense landuse practices support our argument that vegetation changes along Wapanocca Bayou were caused by prehistoric anthropogenic disturbances, rather than natural processes associated with oxbow infilling and terrestrialization. With time the role of the natural vegetation succession receded in relative importance as local ecosystems were progressively modified by prehistoric Native Americans. This change was then sustained by intensified historical agricultural practices.