Adolescents are a crucial generation, with the potential to bring future social and economic success for themselves and their countries. More than 90% of adolescents living with HIV reside in sub-Saharan Africa, where their mental health is set against a background of poverty, familial stress, service gaps, and an HIV epidemic that is now intertwined with the COVID-19 pandemic. In this Series paper, we review systematic reviews, randomised trials, and cohort studies of adolescents living with and affected by HIV. We provide a detailed overview of mental health provision and collate evidence for future approaches. We find that the mental health burden for adolescents living with HIV is high, contributing to low quality of life and challenges with adherence to antiretroviral therapy. Mental health provision is scarce, infrastructure and skilled providers are missing, and leadership is needed. Evidence of effective interventions is emerging, including specific provisions for mental health (eg, cognitive behavioural therapy, problem-solving, mindfulness, and parenting programmes) and broader provisions to prevent drivers of poor mental health (eg, social protection and violence prevention). We provide evidence of longitudinal associations between unconditional government grants and improved mental health. Combinations of economic and social interventions (known as cash plus care) could increase mental health benefits. Scalable delivery models include task sharing, primary care integration, strengthening families, and a pyramid of provision that differentiates between levels of need, from prevention to the care of severe disorders. A turning point has now been reached, from which complacency cannot persist. We conclude that there is substantial need, available frameworks, and a growing evidence base for action while infrastructure and skill acquisition is built.