ABSTRACT Objective As substance use disorders are globally among the top causes of preventable mortality and morbidity among adolescents, there is a need for developing effective prevention programs to address the rising prevalence and the associated health consequences. The main aim of this study is to develop a community-based study protocol for preventing substance use in Iranian adolescents. Methods and results An ecological approach, mobilizing for action through planning and partnership (MAPP), was used to develop a study protocol for preventing substance use among 14–18-year-old adolescents participating in this study. Participants were randomized to the intervention (n = 70) or control (n = 70) groups. The intervention group was exposed to eight individual sessions by two qualified trainers over eight weeks to stimulate (1) positive outcome expectations, (2) self-efficacy, e.g., to resist social pressure, (3) self-regulation, e.g., by self-monitoring of stress and emotions. Outcomes were assessed by the percentage reduction in substance use after six, 18, and 24 months after the intervention. Discussion In this study, we have been to outline and explain the steps of developing and implementing a community-based study protocol. This protocol, if practical and effective, could be easily implemented in various settings and would reach large numbers of young people cost-effectively.