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There is currently no consensus on the importance of climate change in Mesoamerican prehistory. Some invoke drought as a causal factor in major cultural transitions, including the abandonment of many sites at 900 CE, while others conclude that cultural factors were more important. This lack of agreement reflects the fact that the history of climate change in many regions of Mesoamerica is poorly understood. We present paleolimnological evidence suggesting that climate change was important in the abandonment of Cantona between 900 CE and 1050 CE. At its peak, Cantona was one of the largest cities in pre-Columbian Mesoamerica, with a population of 90,000 inhabitants. The site is located in the Cuenca Oriental, a semiarid basin east of Mexico City. We developed a subcentennial reconstruction of regional climate from a nearby maar lake, Aljojuca. The modern climatology of the region suggests that sediments record changes in summer monsoonal precipitation. Elemental geochemistry (X-ray fluorescence) and delta O-18 from authigenic calcite indicate a centennial-scale arid interval between 500 CE and 1150 CE, overlaid on a long-term drying trend. Comparison of this record to Cantona’s chronology suggests that both the city’s peak population and its abandonment occurred during this arid period. The human response to climate change most likely resulted from the interplay of environmental and political factors. During earlier periods of Cantona’s history, increasing aridity and political unrest may have actually increased the city’s importance. However, by 1050 CE, this extended arid period, possibly combined with regional political change, contributed to the city’s abandonment.