This research attempts to describe the role of non-human beings in the Spanish Conquista of the Americas during the 16th century, especially in the South American Andes, ruled by the Tawantinsuyu or Empire of the Incas. We aim to conduct an analysis of the ways in which Andean people interpreted the presence of new diseases as a consequence of Christianity and the campaigns to extirpate idolatries, how they consequently organized resistance, and elaborated discourses based on their own cosmovision. In these discourses, the guacas, non-human beings of the territory, emerged as the main political actors that led the resistance against colonizers and the Christian God, whose voices and agency were interpreted by the leaders of the Taki Onqoy Movement and transmitted to the Andean people. Thus, our research focuses on the agency of two non-human agents: microorganisms (like the virus of smallpox) and guacas. The former have been studied mostly by the history of medicine and science, and the latter by religious studies or ethnohistory. Problematizing these approaches, our analysis seeks to elaborate a hybrid framework that goes beyond the modern division of culture and nature, proposing a perspective that considers the emergence of indigenous cosmopolitics, by recognizing the heterogeneity and multiplicity of the historical and the political.