School-based health interventions can help prevent adolescent substance use, but their success depends on various factors affecting planning and evaluation. This study examines the factors that facilitate or hinder the success of school-based digital health interventions. A systematic review was conducted in September-October 2024, following PRISMA guidelines, using PubMed, Scopus, Web of Science, CINAHL, and PsycINFO databases. From a total of 2530 studies, after removing duplicates and screening titles and abstracts, 51 full-text articles were assessed and 12 met the inclusion criteria. Data were extracted using an adapted tool for systematic reviews applying the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. The methodological quality was assessed with Joanna Briggs Institute tools. The studies included cluster-randomized controlled trials, quasi-experimental designs, and one cross-sectional study, primarily targeting adolescents aged 11.9-17.4 years, with sample sizes ranging from 90 to nearly 5000 participants. Most interventions were implemented in schools in the USA, Europe, and Taiwan, with balanced gender distribution. Many studies reported on reach and effectiveness in reducing substance use, particularly alcohol. However, adoption and implementation factors influencing school participation were less frequently addressed, and maintenance was not mentioned. To maximize impact, future efforts should focus on enhancing sustainment and participation by leveraging emerging technologies for personalization.