This talk addresses how indigenous populations of colonial Yucatán lived with and negotiated interwoven recurring crises of epidemic diseases, environmental disasters, and economic calamities. In particular, using Mayalanguage medical records from the Ayer collection detailing sixteenth and seventeenth century outbreaks, it examines how syndemic crises of disease and natural disasters shaped the nature and production of knowledge alongside colonial relations. Shared experiences with disease allowed for cross-cultural interactions that positioned native peoples—supposedly subjugated populations—at the center of colonial systems of medicine that were rooted in indigenous ideas, traditions and practices.