Although previous research has identified links between parenting and adolescent substance use, little is known about the role of adolescent individual processes, such as sensation seeking, and temperamental tendencies for such links. To test tenets from biopsychosocial models of adolescent risk behavior and differential susceptibility theory, this study investigated longitudinal associations among positive and harsh parenting, adolescent sensation seeking, and substance use and tested whether the indirect associations were moderated by adolescent temperament, including activation control, frustration, sadness, and positive emotions. Longitudinal data reported by adolescents (n = 892; 49.66% girls) and their mothers from eight cultural groups when adolescents were ages 12, 13, and 14 were used. A moderated mediation model showed that parenting was related to adolescent substance use, both directly and indirectly, through sensation seeking. Indirect associations were moderated by adolescent temperament. This study advances understanding of the developmental paths between the contextual and individual factors critical for adolescent substance use across a wide range of cultural contexts.