PEPFAR (President's Emergency Plan for AIDS Relief), a landmark US foreign health policy, is recognised for saving 26 million lives from HIV. PEPFAR investments have also had life-saving impacts for children across sub-Saharan Africa through childhood HIV prevention, care, and treatment, ensuring 7·8 million babies were born HIV-free, supporting 13 million orphaned and vulnerable children, and protecting 10·3 million girls from sexual abuse. In this Health Policy, we review data from UNAIDS, UNICEF, World Bank, Violence Against Children Surveys, SPECTRUM model data, and Population-based HIV Impact Assessments; synthesise PEPFAR reports; conduct in-depth interviews; search PubMed for programme effectiveness evidence; and review economic reports. PEPFAR support is associated with substantial collateral benefits for the USA and Africa, including a four-fold increase in export of US goods to Africa, and US$71·6 billion in total goods trade between the USA and Africa in 2024. PEPFAR-supported countries in Africa are committed to ownership of HIV responses by 2030-overall, PEPFAR-supported countries in sub-Saharan Africa have progressively increased their co-financing of their health systems through domestic government and private expenditure from $13·7 billion per year in 2004 to $42·6 billion per year in 2021. The feasibility of a 5-year transition to country-led sustainability is supported by evidence of innovative cost-saving models of delivery, including through faith-based and community-based organisations, and high return-on-investment for PEPFAR programmes. There are also collateral benefits of PEPFAR for US and Africa national security and health security, for example, reducing forced migration and increasing capacity to control emerging transborder infectious disease threats. Risks in sub-Saharan Africa remain acute: one in five girls (younger than 18 years) experience rape or sexual assault; one in ten children (younger than 18 years) are orphaned; and a child (younger than 15 years) is estimated to die from AIDS every 7 min. Without continued PEPFAR programmes, models predict that by 2030, an additional 1 million children will become infected with HIV, 0·5 million additional children will die of AIDS, and 2·8 million children will additionally become orphaned by AIDS. There is now an opportunity for a transformational partnership between the USA and Africa, to accelerate domestic government co-financing, private-sector investments, and charitable foundations. A 5-year progressive runway of transition can occur through continued authorisation of PEPFAR programmes, which can lead to the end of AIDS for children and families, an historic achievement.