BACKGROUND: Men who have sex with men (MSM) face disproportionate risks concerning HIV and other sexually transmitted infections, substance use, and mental health. These outcomes constitute an interacting syndemic among MSM; interventions addressing all 3 together could have multiplicative effects. eHealth interventions can be accessed privately, and evidence from general populations suggests these can effectively address all 3 health outcomes. However, it is unclear how useable, accessible, or acceptable eHealth interventions are for MSM and what factors affect this. OBJECTIVE: We undertook a systematic review of eHealth interventions addressing sexual risk, substance use, and common mental illnesses among MSM and synthesized evidence from process evaluations. METHODS: We searched 19 databases, 3 trials registers, OpenGrey, and Google, and supplemented this by reference checks and requests to experts. Eligible reports were those that discussed eHealth interventions offering ongoing support to MSM aiming to prevent sexual risk, substance use, anxiety or depression; and assessed how intervention delivery or receipt varied with characteristics of interventions, providers, participants, or context. Reviewers screened citations on titles, abstracts, and then full text. Reviewers assessed quality of eligible studies, and extracted data on intervention, study characteristics, and process evaluation findings. The analysis used thematic synthesis. RESULTS: A total of 12 reports, addressing 10 studies of 8 interventions, were eligible for process synthesis. Most addressed sexual risk alone or with other outcomes. Studies were assessed as medium and high reliability (reflecting the trustworthiness of overall findings) but tended to lack depth and breadth in terms of the process issues explored. Intervention acceptability was enhanced by ease of use; privacy protection; use of diverse media; opportunities for self-reflection and to gain knowledge and skills; and content that was clear, interactive, tailored, reflective of MSM's experiences, and affirming of sexual-minority identity. Technical issues and interventions that were too long detracted from acceptability. Some evidence suggested that acceptability varied by race or ethnicity and educational level; findings on variation by socioeconomic status were mixed. No studies explored how intervention delivery or receipt varied by provider characteristics. CONCLUSIONS: Findings suggest that eHealth interventions targeting sexual risk, substance use, and mental health are acceptable for MSM across sociodemographic groups. We identified the factors shaping MSM's receipt of such interventions, highlighting the importance of tailored content reflecting MSM's experiences and of language affirming sexual-minority identities. Intervention developers can draw on these findings to increase the usability and acceptability of integrated eHealth interventions to address the syndemic of sexual risk, substance use, and mental ill health among MSM. Evaluators of these interventions can draw on our findings to plan evaluations that explore the factors shaping usability and acceptability.