Objective: To evaluate the substance use pathways of minority adolescents with a structural equation modeling (SEM) based on the social ecological model. Method: Seven hundred ninety adolescents completed the baseline survey questionnaire for the Center for Substance Abuse Prevention's Mentoring and Family Strengthening Initiative. The exogenous variables were family supervision, family involvement, and social support, whereas self-control, school connectedness, and substance use served as the endogenous variables. Results: The following significant direct effects were found: family involvement to self-control; self-control and social support to school connectedness; school connectedness to substance use. Conclusions: These findings provide empirical evidence that family protective factors can significantly influence adolescents' substance use and should be adopted into substance use prevention interventions.