Initiation of substance use often occurs earlier among American Indian (AI) youth than among other youth in the USA, bringing increased risk for a variety of poor health and developmental outcomes. Effective prevention strategies are needed, but the evidence base remains thin for this population. Research makes clear that prevention strategies need to be culturally coherent; programs with an evidence base in one population cannot be assumed to be effective in another. However, guidance on effective adaptation is lacking. This paper reports on cultural adaptation of an evidence-based program utilizing the multiphase optimization strategy (MOST) framework embedded within a community-engaged process to evaluate intervention components. The Strengthening Families Program for Parents and Youth 10-14 was adapted to become the Thiwáhe Gluwáš'akapi Program for American Indian youth and families. Three program components were evaluated for their effectiveness with regard to outcomes (youth substance use, theoretical mediators of program effects on substance use, and program attendance) in a sample of 98 families (122 youth and 137 adults). Consistent with the MOST framework, the value of components was also evaluated with regard to efficiency, economy, and scalability. Expanding on the MOST framework for cultural adaptation, we also considered the results of the MOST findings regarding the acceptability of each component from the perspectives of community members and participants. The promise of a strategic component-based approach to adapting evidence-based interventions is discussed, including the benefits of engaging community to ensure relevance and considering both cultural and scientific rationale for each component to enhance impact.