Background: The aim of this mixed-methods, systematic literature review was to develop an understanding of the factors affecting the implementation of tobacco and substance use intervention programmes in the secondary school setting using NPT as an analytical framework. Methods: A search strategy was developed that combined implementation, school and intervention search terms. Literature searches were conducted in MEDLINE, Embase, PsycHINFO, Scopus, ERIC, CINAHL, Web of Science and the Cochrane Library. PROSPERO was also searched for similar systematic reviews and a grey literature search of policy documents and relevant material was also conducted. Papers were eligible for inclusion if they were based in a secondary school and focused on the implementation of a tobacco or substance use programme. Both quantitative and qualitative methodologies were considered for inclusion. Normalisation Process Theory (NPT) was used as a conceptual framework to identify facilitators and barriers of implementation and to structure the synthesis. Results: Inclusion criteria were met by 15 papers. The included papers were both quantitative and qualitative and focused on a range of tobacco and substance use interventions, delivered by differing providers. Key facilitating factors for implementation were positive organisational climate, adequate training and teacher's and pupil's motivation. Barriers to implementation included heavy workloads, budget cuts and lack of resources or support. Quality appraisal identified papers to be of moderate to weak quality, as papers generally lacked detail. Conclusion: NPT highlighted the need for studies to extend their focus to include reflexive monitoring around appraisal and the evaluation processes of implementing new tobacco or substance use programs. Future research should also focus on employing implementation theory as a tool to facilitate bridging the gap between school health research and practice.