Background Human immunodeficiency virus/sexually transmitted infections, sexual risk, substance (alcohol and other legal and illegal drugs) use and mental ill health constitute a ‘syndemic’ of mutually reinforcing epidemics among men who have sex with men. Electronic health (e-health) interventions addressing these epidemics among men who have sex with men might have multiplicative effects. To our knowledge, no systematic review has examined the effectiveness of such interventions on these epidemics among men who have sex with men. Objective The objective was to synthesise evidence addressing the following: (1) What approaches and theories of change do existing e-health interventions employ to prevent human immunodeficiency virus/sexually transmitted infections, sexual risk, alcohol/drug use or mental ill health among men who have sex with men? (2) What factors influence implementation? (3) What are the effects of such interventions on the aforementioned epidemics? (4) Are such interventions cost-effective? Data sources A total of 24 information sources were searched initially (October–November 2018) [the following sources were searched: ProQuest Applied Social Sciences Index and Abstracts; Campbell Library; EBSCO Cumulative Index to Nursing and Allied Health Literature Plus, Wiley Online Library The Cochrane Library; Centre for Reviews and Dissemination databases (the Database of Abstracts of Reviews of Effects and the NHS Economic Evaluation Database); the Health Technology Assessment database; Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) database of health promotion research (Bibliomap); ProQuest Dissertations & Theses Global; OvidSP EconLit; OvidSP EMBASE; OvidSP Global Health; OvidSP Health Management Information Consortium; ProQuest International Bibliography of the Social Sciences; Ovid MEDLINE ALL; OvidSP PsycINFO; Web of Science Science Citation Index Expanded; Elsevier Scopus; OvidSP Social Policy & Practice; Web of Science Social Sciences Citation Index Expanded; ProQuest Sociological Abstracts; ClinicalTrials.gov; World Health Organization International Clinical Trials Registry Platform; EPPI-Centre Trials Register of Promoting Health Interventions; and the OpenGrey database], and an updated search of 19 of these was conducted in April 2020. Reference lists of included reports were searched and experts were contacted. Review methods Eligible reports presented theories of change and/or process, outcome and/or economic evaluations of e-health interventions offering ongoing support to men who have sex with men to prevent human immunodeficiency virus/sexually transmitted infections, sexual risk behaviour, alcohol/drug use and/or common mental illnesses. References were screened by title/abstract, then by full text. Data extraction and quality assessments used existing tools. Theory and process reports were synthesised using qualitative methods. Outcome and economic data were synthesised narratively; outcome data were meta-analysed. Results Original searches retrieved 27 eligible reports. Updated searches retrieved 10 eligible reports. Thirty-seven reports on 28 studies of 23 interventions were included: 33 on theories of change, 12 on process evaluations, 16 on outcome evaluations and one on an economic evaluation. Research question 1: five intervention types were identified – ‘online modular’, ‘computer games’ and ‘non-interactive’ time-limited/modular interventions, and open-ended interventions with ‘content organised by assessment’ and ‘general content’. Three broad types of intervention theories of change were identified, focusing on ‘cognitive/skills’, ‘self-monitoring’ and ‘cognitive therapy’. Research question 2: individual tailoring based on participant characteristics was particularly acceptable, and participants valued intervention content reflecting their experiences. Research question 3: little evidence was available of effects on human immunodeficiency virus or sexually transmitted infections. The analysis did not suggest that interventions were effective in reducing instances of human immunodeficiency virus or sexually transmitted infections. The overall meta-analysis for sexually transmitted infections reported a small non-significant increase in sexually transmitted infections in the intervention group, compared with the control group. Meta-analyses found a significant impact on sexual risk behaviour. The findings for drug use could not be meta-analysed because of study heterogeneity. Studies addressing this outcome did not present consistent evidence of effectiveness. Trials did not report effects on alcohol use or mental health. Research question 4: evidence on cost-effectiveness was limited. Limitations The quality of the eligible reports was variable and the economic synthesis was limited to one eligible study. Conclusions There is commonality in intervention theories of change and factors affecting receipt of e-health interventions. Evidence on effectiveness is limited. Future work Future trials should assess the impact of interventions on multiple syndemic factors, among them sexual risk, substance use and mental health; incorporate sufficient follow-up and sample sizes to detect the impact on human immunodeficiency virus/sexually transmitted infections; and incorporate rigorous process and economic evaluations. Study registration This study is registered as PROSPERO CRD42018110317. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full inPublic Health Research; Vol. 10, No. 4. See the NIHR Journals Library website for further project information.