The overall objective of this study was to examine the effects of an innovative culturally appropriate school‐based intervention. Cherokee Talking Circle (CTC), for the prevention of substance use among 100 Keetoowah‐Cherokee 6th graders as they transition to middle school. The impact of the CTC on substance use involvement (measured by the Global Assessment of Individual Needs – Quick) and Cherokee self‐reliance (measured by the Cherokee Self‐Reliance Questionnaire) was assessed using a two‐condition quasi‐experimental design, comparing the CTC to standard substance use education (SE). Findings from this study suggest that prevention from a cultural perspective is an obvious course of action against substance use among Native American early adolescents.