This article balances current understandings of the political landscape of Postclassic Mesoamerica through a conjunctive analysis of the archaeology and ethnohistory of the Mixtec Empire of Tututepec in the lower Río Verde region of Oaxaca. Tututepec has long been known from ethnohistoric sources as a powerful Late Postclassic imperial center. Until recently, however, little has been known of the archaeology of the site. We discuss the founding, extent, chronology, and aspects of the internal organization and external relations of Tututepec based on the results of a regional survey, excavations, and a reanalysis of ethnohistoric documents. Tututepec was founded early in the Late Postclassic period when the region was vulnerable to conquest due to political fragmentation and unrest. Indigenous historical data from three Mixtec codices narrate the founding of Tututepec as part of the heroic history of Lord 8 Deer “Jaguar Claw.” According to these texts, Lord 8 Deer founded Tututepec through a creative combination of traditional Mixtec foundation rites and a strategic alliance with a highland group linked to the Tolteca-Chichimeca. Archaeological and ethnohistoric evidence indicate that Tututepec continued to expand through the Late Postclassic, growing to 21.85 km2, and at its peak was the capital of an empire extending over 25,000 km2.