BackgroundEarly substance use disproportionately impacts Native American (Native) youth and increases their risk for future abuse and dependence. The literature urges for interventions to move beyond focusing on single risk behaviors (e.g. substance use) and instead have capacity to improve health risk behaviors co-occuring during adolescence, particularly among Native populations for whom few evidence-based interventions (EBI) exist. We evaluated the effectiveness of the Respecting the Circle of Life program (RCL) on risk and protective factors for early substance use. RCL is a culturally tailored EBI shown to improve sexual health outcomes among Native youth. MethodsWe conducted secondary analyses of data collected through a community-based randomized controlled trial of RCL evaluated among Native youth (ages 11–19) residing on a rural reservation between 2015–2020 (N = 534, 47.4 % male). We used linear regression, controlling for baseline age and sex, to test between study group differences in outcomes at 3-, 9-, and 12-month post-intervention. Models were stratified by sex and age (11−12, 13−14, and 15+ years of age) to examine differences within these subgroups. ResultsYouth receiving RCL reported lower intention to use substances through 12-months follow-up (p = 0.006). Statistically significant improvements were also observed across peer, parent, and sexual partner risk and protective factors to delay substance use initiation, with notable differences among boys and participants ages 13−14. ConclusionsRCL is a primary prevention, skills-based program effective in preventing risks for substance use. This evaluation underscores the value in developing programs that influence concurrent adolescent risk behaviors, especially for Native communities who endure multiple health disparities.