This paper describes a poverty reduction approach to addressing an important determinant of health and well-being among Canada’s First Nations. The Poverty Action Research Project (PARP) has its origins in the Make Poverty History Committee established by the Assembly of First Nations (AFN) in 2008. Academic members of the Committee in cooperation with the AFN subsequently applied for an action research grant to the Canadian Institutes of Health Research (CIHR). The project selected five volunteer First Nations from different parts of Canada, hiring a coordinator in each, undertaking background research, developing a profile and working with First Nation representatives in the development of a strategy to address upstream determinants of health and well-being. Subsequently, project team members within each region assisted where needed with plan implementation, supporting some initiatives with small grants. This paper provides insights from the project in several key areas, including First Nation rejection of the concept of poverty as usually defined, the importance of taking action to strengthen collectivities as well as individuals, the feasibility of assisting First Nations who are at different points in their development journey, the strengths of the leadership within the First Nations, and finding the appropriate balance between the elected and business leadership. These insights emerged from dialogue and reflection among project team members and community participants over the life of the project. We also describe what we have learned about how to engage effectively and with mutual respect with First Nations in this kind of project. The paper concludes with a review of our experiences with the policies and practices of the national research granting councils and the universities, which have not fully adjusted to the requirements of action research involving First Nations.