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The occupation history of the Cahokia archaeological complex (ca. AD 1050–1400) has received significant academic attention for decades, but the subsequent repopulation of the region by indigenous peoples is poorly understood. This study presents demographic trends from a fecal stanol population reconstruction of Horseshoe Lake, Illinois, along with information from archaeological, historical, and environmental sources to provide an interpretation of post-Mississippian population change in the Cahokia region. Fecal stanol data indicate that the Cahokia region reached a population minimum by approximately AD 1400, regional population had rebounded by AD 1500, a population maximum was reached by AD 1650, and population declined again by AD 1700. The indigenous repopulation of the area coincides with environmental changes conducive to maize-based agriculture and bison-hunting subsistence practices of the Illinois Confederation. The subsequent regional depopulation corresponds to a complicated period of warfare, epidemic disease, Christianization, population movement, and environmental change in the eighteenth century. The recognition of a post-Mississippian indigenous population helps shape a narrative of Native American persistence over Native American disappearance.