School-based substance use prevention programmes vary in effectiveness, and implementation quality is a key determinant of success. This systematic review and narrative synthesis aimed to identify features of post-primary school-based substance use prevention programmes that facilitate or hinder implementation. A systematic literature search was conducted across multiple electronic databases, yielding 9586 articles. After duplicates were removed, four investigators independently screened titles, abstracts, and full texts, resolving conflicts collaboratively. Inclusion criteria were quantitative or qualitative peer-reviewed studies addressing barriers and facilitators to implementing school-based substance use prevention programmes. Studies focusing solely on nicotine products, protocols, or reviews were excluded. Data were extracted, methodologically assessed using a validated appraisal tool, and analysed through narrative synthesis. The review protocol was not pre-registered. No funding was received, and the authors declare no competing interests.

Twenty studies met the inclusion criteria, including quantitative, qualitative, and mixed-method designs, from diverse geographic regions. Four key components of programme implementation emerged: fidelity and adherence; programme feasibility and suitability; additional support; and teacher and student characteristics. Findings highlighted the importance of age-appropriate interactive design, supportive school environments, sustained teacher training, cultural appropriateness, and flexibility to maintain programme fidelity. Practical guidance for programme developers and school leaders includes designing flexible programmes that maintain core components while accommodating real-world school constraints. Limitations include inconsistent use of implementation frameworks and variability in methodological rigour. These findings underscore the importance of structured implementation, teacher support, and adaptability in school-based substance use prevention programmes.