Understanding human-wildlife relationships and interactions is crucial to implementing policies and practices related to wildlife and public health that are locally relevant and adapted to local communities and needs. With the goal of informing a community-based participatory muskox health surveillance system in the community of Iqaluktutiaq (Cambridge Bay) on Victoria Island, Nunavut, Canada, we explored the importance of muskoxen for community residents, their relevance for local food security, and the relationships and interactions between Iqaluktutiamiut and muskoxen. We investigated these themes through individual interviews of 30 community members identified as muskox experts by local organizations. Results were finalized and refined with 26 interviewees in feedback sessions. For Iqaluktutiaq residents, muskoxen have nutritional, economic, sociocultural, and environmental importance. The decline of muskoxen documented locally has a multidimensional impact on the community, with negative effects on all the domains explored, from food security to the integrity of the cultural system. Descriptions of subsistence and commercial harvesting and butchering practices are an asset for the successful implementation of participatory muskox health surveillance activities (e.g., hunter-based sampling), as well as for interpretation of derived data (e.g., local knowledge on muskox diseases). Knowledge of specific harvesting practices that might increase exposure to zoonotic agents is also relevant for designing targeted strategies to mitigate public health risks. This research underlines how careful examination of the human-wildlife context through local perspectives can benefit wildlife health surveillance, public health, and wildlife co-management outcomes.