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The North faces significant health disparities, especially among its many Indigenous peoples. In this article we discuss historical, environmental, and cultural variables that contribute to these disparities and propose a One Health approach to address them in a holistic and culturally appropriate manner. The One Health paradigm recognizes the interdependence among the health and well-being of people, animals and the environment. As such, the framework aligns well with many Indigenous world views. This proactive, interdisciplinary, constructivist, and collaborative approach promise earlier detection of risks and threats, as well as more effective responses, in part by engaging community level stakeholders in all stages of the process. In the far North, humans, especially Indigenous peoples, continue to live closely connected to their environment, in settings that exert significant impacts on health. In recent decades, rapid warming and elevated contaminant levels have heightened environmental risks and increased uncertainty, both of which threaten individual and community health and well-being. Under these circumstances especially, One Health's comprehensive approach may provide mitigating and adaptive strategies to enhance resilience. While many of the examples used in this manuscript focus on Alaska and Canada, the authors believe similar conditions exist among the indigenous and rural residents across the entire Circumpolar North.