Research points toward multiple pathways (i.e., psychosocial domains) through which religiosity influences substance use behaviors. This study examined whether refusal efficacy mediated the relationship between religiosity and substance use in African-American adolescents and young adults. Four hundred thirty-five urban and rural African-Americans, aged between 12 and 25, completed measures of private and public religiosity, refusal efficacy, and substance use (i.e., tobacco, alcohol, marijuana, and other illicit drug use). Tests for mediation were computed with private and public religiosity as independent variables, drug refusal efficacy as mediator, and substance use as the criterion. Results show that drug refusal efficacy mediated the relationship between private religiosity and tobacco, marijuana, and other illicit drug use, but not for alcohol use. Refusal efficacy also mediated the relationship between public religiosity and alcohol use, but not for other licit and illicit substances. The findings provide support for the unique impact of public religiosity when considering its role in preventive intervention. Future research should consider examining other psychosocial domains which may mediate the effect of religiosity on substance use behaviors among African-American adolescents.