This study systematically reviewed research on the use of digital game approaches for the prevention, assessment, and treatment of substance use and positive development in adolescents. Background/Objectives: This study aimed to identify and summarize gaps in the published literature on game-based digital interventions for substance use and positive development for adolescents through a systematic review. Methods: Following PRISMA guidelines, 26 studies were selected for final analysis from an initial screening of 1601 references. Data were coded for multiple components, including study characteristics, intervention types, intervention contents, sample characteristics, substance use, positive development details, measurement tools, and main findings, particularly emphasizing the effectiveness of game-based digital interventions and the facilitators and barriers affecting program effectiveness. Results: Regarding substance use, 50% of studies reported game-based digital interventions as effective in reducing substance use, 16.7% as partially effective, and 33.3% as not effective. For attitudes toward substance use, 65.0% demonstrated statistical effectiveness, 25.0% indicated partial effectiveness, and 10% found no significance. Among studies that included a positive development component, 35.7% were effective, 50% were partially effective, and 14.3% were not effective. Very few studies have explored the facilitators and barriers to program effectiveness without statistical verification. Conclusions: This study offers valuable insights into the development and validation of game-based digital interventions, thereby establishing a robust foundation for their efficacy.