Extant literature suggests that religiousness is inversely related to adolescent substance use; yet, no systematic investigation has examined whether religiousness may be a protective factor against substance use in the presence of risk factors. We examined whether religiousness moderates the links between parents' psychological and physical aggression and adolescent substance use directly and indirectly through adolescent self-control. The sample comprised adolescents (n = 220, 45% female) and their primary caregivers. Structural equation modeling analyses suggested that adolescents with low religiousness were likely to engage in substance use when subjected to harsh parenting, but there was no association between harsh parenting and substance use among adolescents with high religiousness. Furthermore, although harsh parenting was related to poor adolescent self-control regardless of religiousness levels, poor self-control was significantly related to substance use for adolescents with low religiousness, whereas the link between poor self-control and substance use did not exist for adolescents with high religiousness. The findings present the first evidence that adolescent religiousness may be a powerful buffering factor that can positively alter pathways to substance use in the presence of risk factors such as harsh parenting and poor self-control.