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A number of competing hypotheses, including hydroclimatic variations, environmental degradation and disturbance, and sociopolitical disintegration, have emerged to explain the dissolution of Cahokia, the largest prehistoric population center in the United States. Because it is likely that Cahokia's decline was precipitated by multiple factors, some environmental and some societal, a robust understanding of this phenomenon will require multiple lines of evidence along with a refined chronology. Here, we use fecal stanol data from Horseshoe Lake, Illinois, as a population proxy for Cahokia and the broader Horseshoe Lake watershed. We directly compare the fecal stanol data with oxygen stable-isotope and paleoenvironmental data from the same sediment cores to evaluate the role of flooding, drought, and environmental degradation in Cahokia's demographic decline and sociopolitical reorganization. We find that Mississippi River flooding and warm season droughts detrimental to agriculture occurred circa (ca.) 1150 CE and possibly generated significant stress for Cahokia's inhabitants. Our findings implicate climate change during the Medieval Climatic Anomaly to Little Ice Age transition as an important component of population and sociopolitical transformations at Cahokia, and demonstrate how climate transitions can simultaneously influence multiple environmental processes to produce significant challenges to society.