Background: Effective school-based programs for preventing substance abuse offer considerable public health potential. Yet limited class time and uneven implementation fidelity can be barriers to widespread adoption and high-quality implementation. A hybrid digital approach may be effective and help address these barriers., Objective: To evaluate the effectiveness of a hybrid substance abuse prevention program for middle school students consisting of e-learning modules and in-person class sessions., Design: Twenty-three United States (U.S.) middle schools were randomly assigned either to an intervention condition (13 schools) or a treatment-as-usual control condition (10 schools) where standard health education material was delivered. There were 1,447 participants who completed the pre-test and post-test assessments, of which 48.3% were male and 51.7% female., Intervention: The hybrid digital intervention consisted of 14 brief e-learning modules and six classroom sessions adapted from an evidence-based program designed for classroom implementation to increase knowledge of adverse consequences of substance use and improve social skills, personal coping skills, and skills for resisting social influences to smoke, drink, or use drugs., Measures: Participating students completed online pre-test and post-test surveys to assess substance use, knowledge, and life skills., Results: There were significant reductions in substance use for the hybrid digital condition compared to the control condition as well as significant increases in health knowledge, skills knowledge, and life skills., Conclusions: A hybrid digital approach to substance abuse prevention is effective and offers potential for overcoming common barriers to widespread adoption and high-quality implementation., Competing Interests: Authors CW, CB, SS, and GB are employees at National Health Promotion Associates (NHPA), which markets the program adapted and tested in this project. Author KG is a former employee of NHPA and currently serves as a consultant to NHPA., (Copyright © 2022 Griffin, Williams, Botvin, Sousa and Botvin.)