Antisocial peer behavior and low parental knowledge of adolescents' activities are key interpersonal risk factors for adolescent substance use. However, how the magnitude of associations between these risk factors and substance use may vary across adolescence remains less well understood. The present study examined the age-varying associations of parental knowledge and antisocial peer behavior with adolescents' substance use (i.e., cigarette use, drunkenness, and marijuana use) using time-varying effect modeling. Using data from the Promoting School-Community-University Partnerships to Enhance Resilience (PROSPER) study, the final sample consists of 8,222 adolescents, followed from Grade 6 to Grade 12 (age 11 to age 18.9), including those who newly joined the schools at the targeted grade levels. Results showed that low parental knowledge and antisocial peer behavior were significantly associated with the use of each of the three substances across the majority of adolescence. The magnitude of the associations between substance use and both risk factors decreased across age, except between peer risk and marijuana use. Further, there was a significant interaction between parent and peer risk factors such that low parental knowledge was less strongly associated with substance use at higher levels of antisocial peer behavior. Findings highlighted early adolescence as an important period to target parent and peer prevention and interventions for reducing early substance use.