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This paper examines how knowledge about Brazil’s natural environments was produced in early modern contexts, highlighting the complex and entangled interactions between Europeans and Indigenous populations. Its originality lies in recentring Indigenous epistemologies as active forces within the making of modern science, rather than treating them as peripheral sources of empirical information. The central question guiding the study is how cross-cultural encounters in coastal, riverine, and Amazonian “contact zones” shaped the construction, circulation, and transformation of knowledge in the early modern period. Methodologically, the research examines sixteenth- to eighteenth-century documentary sources produced in Brazil, encompassing early coastal accounts and later works of Enlightenment natural history. These materials are approached through a transdisciplinary framework that brings together insights from the history of knowledge, the social history of science, and anthropology. The analysis underscores the asymmetrical power dynamics that shaped these encounters, while revealing that knowledge circulated in multiple directions and was continually reconfigured through transcultural processes. The results suggest that knowledge in early modern Brazil developed through sustained transcultural entanglements involving human and non-human agents, cosmologies, and material practices. By shifting the analytical focus toward local epistemologies, the study presents a critical perspective on early modern science as a syncretic, negotiated, and historically situated enterprise. This approach highlights the broader relevance of Indigenous epistemologies for understanding global histories of knowledge.