Objective: School-based health promotion programs can have a positive effect on behavioral and social outcomes among adolescents. Yet, limited classroom time and suboptimal program implementation can reduce the potential impact of these interventions. In the present randomized trial, we tested the effectiveness of a classroom-based substance use prevention program that was adapted for hybrid implementation. Method: The hybrid adaptation included eight asynchronous e-learning modules that presented didactic content and eight classroom sessions designed to facilitate discussion and practice of refusal, personal self-management, and general social skills. Nineteen high schools were randomly assigned to intervention or control conditions. Students (N = 1,235) completed confidential online pretest and posttest surveys to assess the effects of the intervention on tobacco and alcohol use and life skills. The sample was 50.7% female and 35.5% non-White with a mean age of 15.2 years. Results: Analyses revealed significant program effects on current cigarette smoking, alcohol use, drunkenness, and intentions for future use. There were also program effects for communication, media resistance, anxiety management, and refusal skills. Conclusions: Taken together, these findings suggest that hybrid approaches can produce robust prevention effects and may help reduce barriers to the widespread adoption and implementation of evidence-based prevention programs.