The Baniwa Indigenous people of the upper Rio Negro refer to otters as “Shamans of the Water,” recognizing them as guardians of fish populations. During the mid-20th century, however, intensive hunting for the global fur trade drove otters to near local extinction. Since international wildlife trade bans in the 1970s, otter populations have rebounded, prompting renewed Baniwa reflections on their relationships with these species. In this study, we integrate Indigenous knowledge with ecological data (e.g., spatial-use patterns of otters and humans and diet analyses from fecal samples) to examine human–otter coexistence within an Amazonian Indigenous socioecological system. We analyze spatial overlap and dietary patterns among Baniwa fishers and two other species: Giant Otters (Pteronura brasiliensis) and Neotropical Otters (Lontra longicaudis). Baniwa fishing is concentrated in blackwater lakes, which are also preferred foraging habitats for Neotropical Otters, whereas Giant Otters show limited spatial overlap with human activities. Dietary analyses reveal clear trophic segregation, with Baniwa targeting mid to large-sized fish species and otters feeding primarily on smaller fish. Coexistence is further maintained through mutual avoidance practices, behavioral adjustments, historical memory, and relational understandings that frame otters as guardians of aquatic environments. Our findings suggest that coexistence is both dynamic and emerges from the interaction of ecological differentiation, Indigenous socioecological practices, and historical processes; also highlight the value of Indigenous knowledge for understanding and supporting human-wildlife coexistence in Amazonia.