The objective of this study was to examine whether mother, father, and closest grandparent involvement are associated with South African adolescents’ mental health (internalizing and externalizing problems and prosocial behavior) and substance use. A sample of 512 Grade 8 and Grade 9 learners in Cape Town (M age = 14 years) completed a structured survey. Of the participants, 57% were female, and 85% identified themselves as ‘colored’ (mixed race). Hierarchical multiple regression analyses, controlling for age, sex, and socioeconomic status, indicated that mother and father involvement were negatively associated with adolescents’ internalizing and externalizing problems, whereas mother and closest grandparent involvement were positively associated with prosocial behavior. Hierarchical logistic regression analyses revealed that parent involvement was negatively associated with past-month cigarette use, but not with past-month alcohol or past-year marijuana use. The findings suggest the importance of considering parents and grandparents in interventions to promote adolescent mental health.