Indigenous communities in the United States experience some of the highest rates of food insecurity and diet-related diseases despite an abundance of food assistance programs and other public health interventions. New approaches that center Indigenous perspectives and solutions are emerging and urgently needed to better understand and address these challenges. This Practice Note shares lessons learned from ongoing collaboration between the Karuk Tribe and University of California, Berkeley researchers and other partners to assess and enhance food sovereignty among Tribes and Tribal communities in the Klamath River Basin. Through two participatory research and extension projects, we demonstrate the importance of centering Indigenous knowledge to strengthen research findings and identify more culturally appropriate solutions to community identified food access, health, and ecosystem challenges. Key findings suggest that approaches to food sovereignty and community health must emanate from the community, be approached holistically, reflect community values and priorities, and center Indigenous land stewardship.