Résumé : The Cuenca Oriental, a semi-arid region in east-central Mexico, has long supported complex societies, yet its hydroclimatic variability and human–environment interactions—particularly during the Classic, Postclassic, and Colonial periods—remain poorly understood. Here, we present high-resolution proxy records from Lake Alchichica, a crater lake located 18 km from the ancient city of Cantona (600–1050 CE), to reconstruct environmental conditions in the Cuenca Oriental over the past five millennia. Isotope records reveal three major dry periods: (I) ca. 500–1300 CE, encompassing and extending beyond the Late Classic Drought (770–1100 CE); (II) the 17th century CE, corresponding to a colder phase of the Little Ice Age; and (III) post-1970 CE, coinciding with the peak of ongoing global warming. Anthropogenic indicators—including maize and other anthropogenic pollen, as well as Glomus spores and titanium (Ti) intensity (proxies for soil erosion)—demonstrate sustained human–environment interactions. Maize cultivation began by the mid-first millennium BCE and peaked during the Postclassic period (ca. 1000–1500 CE), followed by a sharp and prolonged decline after the Spanish Conquest, most likely due to demographic collapse driven by the introduction of Old World diseases. Agricultural activity never returned to Postclassic maxima, marking a lasting transformation in land use and food production. Notably, the entire urban lifespan of Cantona was encompassed by the extended drought period (500–1300 CE), and its collapse occurred under climatic conditions comparable to those during its peak. Furthermore, the concurrent intensification of agriculture near Lake Alchichica and the abandonment of Cantona suggest that climate alone does not fully explain the decline of the city, instead pointing to additional factors such as warfare, socio-political instability, and economic disruption.