Background Ensuring young people experience good sexual health is a key public health concern. Yet, some vulnerable groups of young people are at higher risk of poor sexual health, and consequently require additional support to achieve good sexual health. Therefore, the aim of this systematic review was to identify and assess the evidence base for behavioural and psychosocial interventions to improve sexual health for young people with additional vulnerabilities.Methods We searched for randomised controlled trials of interventions aimed at promoting sexual health, with any non-pharmacological comparator (e.g., waitlist control). Key outcomes of interest were indicators of sexual health (e.g., condom use, attitudes to contraception, knowledge of risk). Participants in eligible trials were under 25 years old and in a high-risk group (alcohol and other drug use; justice-involved; homeless; LGBTQI+; mental ill-health; ethnic minority, or out-of-home care). The final literature searches were performed on 16 September 2020, on MEDLINE, PsycINFO, EMBASE, CENTRAL, Web of Science, Scopus and clinical trial registries. Meta-analyses were conducted where possible.Results Forty-seven papers from 46 trials of the 5213 identified met inclusion criteria, with all but one of the included trials conducted in North America. Three focused predominantly on AOD, six on juvenile justice, two on homelessness, five on young men who have sex with men (YMSM), 26 on ethnic minorities, two on mental ill-health, three on out-of-home care, however no trials were identified in LGBTQI + groups outside of YMSM. The 47 included papers had a combined total of 21,543 participants. The vast majority (26/46) of trials were conducted with ethnic minority groups, with most of the interventions delivered as group therapy, and some involving parents and caregivers. Condom use was the most frequently reported outcome measure. In trials targeting ethnic minorities, the meta-analysis found a medium effect size (0.62, p = 0.0004) of the intervention on condom use.Conclusions There remains a dearth of research undertaken outside of North America, and in high-risk groups other than ethnic minorities. Future interventions should address sexual health more broadly than just the absence of negative biological outcomes with LGBTQI+, homeless and mental ill-health populations targeted for such work.This review was registered at Prospero (ref. 149810) and at osf.io/ukva9.