A synthesis of UNICEF’s Eastern and Southern Africa Regional Office Evidence-to-Action research partnership with the University of Oxford and University of Cape Town from 2018 to 2023 was undertaken to identify common themes and generate new insights on: What common factors put adolescents, including adolescents living with HIV and young mothers, at risk of poor health and well-being outcomes? What interventions – alone or in combination – can be implemented at scale to mitigate risk and improve health and well-being outcomes? What are the cross-cutting implications for policy and practice? The synthesis considered secondary data analysis from three longitudinal adolescent cohort studies in South Africa and four systematic reviews on adolescents’ adherence to treatment and retention in care, the effects of decentralizing antiretroviral therapy on health outcomes for adolescents, understanding adolescent mental health in the context of HIV and adolescent pregnancy, and the experiences of adolescent mothers and their children.