Religiousness is reliably associated with lower substance use, but little research has examined whether self-control helps explain why religiousness predicts lower substance use. Building on prior theoretical work, our studies suggest that self-control mediates the relationship between religiousness and a variety of substance-use behaviors. Study 1 showed that daily prayer predicted lower alcohol use on subsequent days. In Study 2, religiousness related to lower alcohol use, which was mediated by self-control. Study 3 replicated this mediational pattern using a behavioral measure of self-control. Using a longitudinal design, Study 4 revealed that self-control mediated the relationship between religiousness and lower alcohol use 6 weeks later. Study 5 replicated this mediational pattern again and showed that it remained significant after controlling for trait mindfulness. Studies 6 and 7 replicated and extended these effects to both alcohol and various forms of drug use among community and cross-cultural adult samples. These findings offer novel evidence regarding the role of self-control in explaining why religiousness is associated with lower substance use.