The literature is equivocal regarding the role of internalizing problems in the etiology of adolescent substance use. In this study, we examined the association of internalizing and externalizing behavior problems and their co-occurrence with early adolescent substance use to help clarify whether internalizing problems operate as a risk or protective factor. A large community sample (N = 387; mean age at the first assessment 12 years old; 83% White/non-Hispanic) was assessed annually for 3 years. Externalizing problem behavior in the absence of internalizing problems showed the strongest prospective association with alcohol, cigarette, and marijuana use. A weaker, albeit statistically significant prospective positive association was found between co-occurring internalizing and externalizing behavior problems and substance use. Internalizing problems in the absence of externalizing problems protected adolescents against cigarette and marijuana use. Clarifying the role of internalizing problems in the etiology of adolescent substance use can inform the development of early intervention and prevention efforts. Our results highlight the importance of further considering the co-occurrence of internalizing and externalizing behavior problems in developmental pathways to substance use.