Background: To determine if school engagement is a viable target for early prevention of adolescent substance use, this study investigated whether school engagement in early adolescence (ages 12-14) is a cause of alcohol and cannabis use during middle to late adolescence (ages 15-19). Methods: To facilitate causal inference, inverse probability of treatment weights (IPTWs), which are based on estimated probabilities of treatment selection (ie, school engagement), were created based on a robust set of potential confounders. Using the IPTWs, a cumulative link mixed model was fit to examine the impact of school engagement on alcohol and cannabis use among an ethnically diverse sample of adolescents (N = 360). Results: School engagement was associated with a lower level of alcohol and cannabis use from age 15 to 18. School engagement was not associated with change in alcohol and cannabis use over time, suggesting that school engagement emits its effect early in the developmental course of substance use and offers protection throughout adolescence. Conclusions: This study supports a compensatory role of early school engagement in substance use across middle and late adolescence. School engagement is a malleable factor and thus offers an avenue for prevention efforts.