Background Schools struggle to timetable health education. Interventions integrating academic and health education to reduce substance use and violence offer promise. No current systematic reviews examine such interventions. Objectives To review evidence to explore the following questions: (1) what types of interventions integrating health and academic education in schools serving those aged 4–18 years have been evaluated? (2) What theories of change inform these interventions? (3) What factors facilitate or limit the successful implementation and receipt of such interventions, and what are the implications for the delivery of such implementations in the UK? (4) How effective are such interventions in reducing smoking and violence and the use of alcohol and drugs, and at increasing attainment? Does this vary by students’ sociodemographic characteristics? (5) What factors appear to influence the effectiveness of such interventions? Data sources In total, 19 databases were searched from 18 November to 22 December 2015, updating searches for outcome evaluations for violence on 28 February 2018 and for substance use on 14 May 2018. References were extracted from included studies and authors contacted. Review methods Included studies reported on theories of change, and process or outcome evaluations of interventions that integrated academic and health education to reduce substance use and/or violence. References were screened on the title/abstract and then on the full report. Data extraction and appraisal used Cochrane, Evidence for Policy and Practice Information Centre and other established tools. Theories of change and process data were qualitatively synthesised. Outcome evaluations were synthesised narratively and meta-analytically. Results In total, 78,451 unique references were originally identified and 62 reports included. Search updates on 28 February and 14 May 2018 retrieved a further 2355 and 1945 references, respectively, resulting in the inclusion of six additional reports. Thirty-nine reports described theories, 16 reports (15 studies) evaluated process and 41 reports (16 studies) evaluated outcomes. Multicomponent interventions are theorised to erode ‘boundaries’ (strengthen relationships) between academic and health education, teachers and students, behaviour in classrooms and in the wider school, and schools and families. Teachers, pro-social peers and parents are theorised to act as role models and reinforcers of healthy behaviours learnt in lessons. There was clear evidence that interventions are facilitated by supportive senior management and alignment with the schools’ ethos, collaborative and supportive teaching environments, and positive pre-existing student, teacher and parent attitudes towards interventions. The barriers were overburdened teachers who had little time to both learn and implement integrated curricula. The strongest evidence for effectiveness was found for the reduction of substance use in school key stages (KSs) 2 and 3. For example, a meta-analysis for substance use at KS3 reported a mean difference of –0.09 (95% confidence interval –0.17 to –0.01). A meta-analysis for effectiveness in reducing violence victimisation in KS2 found no effect. There was mixed evidence for effects on academic outcomes, with meta-analysis precluded by methodological heterogeneity. Limitations Study quality was variable. Integration was sometimes not emphasised in theories of change. Conclusions These interventions are undertheorised but involve multiple forms of boundary erosion. There is clear evidence of characteristics affecting implementation. Interventions are likely to have the greatest impact on substance use. These programmes may be effective in reducing substance use but do not appear to reduce violence and findings on educational impacts are mixed. Future work Future evaluations should assess interventions with clearer theories of change and examine academic outcomes alongside violence and substance use outcomes. Study registration This study is registered as PROSPERO CRD42015026464. Funding The National Institute for Health Research Public Health Research programme.