<p>Prior research has identified externalizing and internalizing pathways to adolescent-onset substance use, but few studies have considered how psychopathology is associated with the development of polysubstance use during early adolescence. This study examined bidirectional associations between substance use patterns with adolescents’ posttraumatic stress symptoms, physical aggression, and delinquent behaviors across two waves of data that were 3 months apart. Participants were 1,811 middle school students (53% female; 72% Black; <i>M</i>_age = 13.1, <i>SD</i>_age = 1.02, range = 10.8 to 16.7) in communities with high rates of violence. Results supported both unique internalizing and externalizing pathways to substance use. Posttraumatic stress and externalizing symptoms each predicted polysubstance use onset (<i>OR</i>s = 1.46 to 2.43), and posttraumatic stress symptoms predicted stability in polysubstance use over time (<i>OR</i>s = 1.45, 1.69). Whereas posttraumatic stress symptoms and delinquent behaviors were uniquely associated with change in substance use patterns (<i>OR</i>s = 1.51 to 2.62), physical aggression was not. Bidirectional associations were not supported, such that youths’ substance use pattern did not predict change in psychopathology over time. Findings illustrate the unique roles of specific forms of internalizing and externalizing psychopathology on early adolescent development of polysubstance use. These results have implications for developmental theory and interventions aiming to prevent onset and escalation of substance use during early adolescence.</p>