The current study included 1,447 students from 23 middle schools across the United States. Schools were randomly assigned to receive the e-learning program and class sessions or serve as a “treatment-as-usual” control group. Compared to controls, students who received the e-learning program and class sessions showed significantly less cigarette smoking, e-cigarette and vaping use, excess alcohol use, marijuana use, and prescription drug misuse. They also showed increased health knowledge and skills knowledge, increased decision-making skills, increased skills related to coping with anxiety and anger, more effective communication and social skills, and increased conflict resolution and assertiveness skills.