<p>Commercial tobacco-related health disparities persist for American Indian and Alaska Natives in the USA despite widespread reductions in commercial tobacco use in the general population. Addressing these disparities requires a culturally relevant approach but the diversity of Tribal communities, including historical, cultural, social, and economic differences, can make uniform public health interventions that are culturally relevant challenging to design. The California Tribal Initiative to Reduce Tobacco-Related Disparities, launched in 2019 by the California Department of Public Health and the California Tobacco Prevention Program, uniquely addresses these disparities by directly funding Tribal governments and American Indian Serving Community Organizations to develop tailored commercial tobacco prevention projects that will work for them. This article presents the results from the California American Indian Tobacco Initiative Evaluation, tasked with assessing the initiative’s success. The study used a longitudinal and mixed-methods approach between 2019 and 2024, employing surveys, key informant interviews, and talking circles to assess the initiative through progress in three areas: enhancing community engagement, advancing and adhering to commercial tobacco prevention policies, and building Tribal capacities to sustain these efforts. Findings indicate significant improvements across all areas, underscoring the efficacy of empowering Tribes to lead health interventions. This approach not only advances public health but also fosters greater trust and collaboration between Tribes and public health entities.</p>