Among youth in Cambodia, there is low awareness of HIV and sexually transmitted infection (STI) risk, and the prevalence of unintended pregnancies is high. We aimed to quantify the health and economic benefits of reaching the 2025 Joint United Nations Programme on HIV/AIDS (UNAIDS) target of 95% coverage of combination HIV prevention/testing packages for young key population groups as well as providing comprehensive sexuality education (CSE) for all youth. The model considered 10–19-year olds in Cambodia, disaggregated by key population group (young men who have sex with men, young transgender persons, young people who use drugs, young female entertainment workers) and in-school/out-of-school status. Three scenarios were projected over 2023–2030: (1) a baseline scenario with fixed intervention coverage; (2) a scenario scaling up existing HIV/STI prevention and testing interventions for young key populations through multiple delivery modalities, plus in-school CSE, over 2024–2025 to reach 95% coverage (maintained until 2030); and (3) scenario 2 plus an additional out-of-school CSE programme for all being implemented and scaled to 95% coverage. HIV infections, unintended pregnancies, maternal deaths and stillbirths averted were converted to economic benefits. Scenario 2 costs US$10.6 million more than the baseline scenario over 2023–2030, and averted 1184 HIV infections, 10 172 unintended pregnancies, 16 maternal deaths and 106 stillbirths. This investment could generate US$36.1 million in economic benefits by 2050, with a benefit–cost ratio of 3.4. Scenario 3, including out-of-school CSE, achieved additional health benefits; however, it was less cost-effective than in-school CSE. Investment in HIV prevention/testing packages for young key population groups and CSE programmes can have favourable returns in Cambodia. Strategies to maintain high levels of school enrolment can facilitate cost-effective ways to expand CSE coverage.