Abstract The presence and sources of pre-Columbian (before 1492 CE) lead (Pb) pollution in the midcontinental United States were investigated using geochemical and Pb isotope analyses on sediment cores recovered from Avery Lake, a floodplain lake located directly adjacent to the Kincaid Mounds archaeological site on the lower Ohio River, Illinois. Geochemical results indicate the presence of Pb pollution during the Baumer (300 BCE to 300 CE) and Mississippian (1150–1450 CE) occupations, and since the 1800s. Pb isotope results link Mississippian Pb pollution to the processing and use of galena primarily from southeastern and/or central Missouri, and to a lesser extent the upper Mississippi River valley, with ∼1.5 t (metric tons) of galena-derived Pb deposited in Avery Lake during this time. Pb pollution during the Baumer phase, equating to ∼0.4 t of Pb, was not accompanied by a Pb isotope excursion and most likely originated from local biomass burning. These results provide new information about the environmental impacts associated with pre-Columbian Native Americans’ interaction with and utilization of their landscape and its resources.