Entrepreneurship education is a strength-based approach and holds promise for promoting health equity for American Indian youth. Arrowhead Business Group (ABG) was developed by a tribal-academic research partnership and is being rigorously evaluated for impacts on psychosocial, behavioral, educational, and economic outcomes. This article describes: 1) the trial design and conceptual model under-girding the ABG program; 2) the sociodemographic, sociocultural, and family/household characteristics of participants at baseline; and 3) the baseline differences in key outcome indicators between study groups. Results demonstrate participants have baseline characteristics appropriate for study aims and are compared and contrasted with other youth from the participating tribal community and state in which the tribe resides. Findings inform future analyses to explore how baseline characteristics are associated with primary and secondary outcomes of the evaluation.