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Background: The absence of high-quality comprehensive civil registration and vital statistics systems across many settings in Africa has led to little empirical data on causes of death in the region. We aimed to use verbal autopsy data to provide comparative, population-based estimates of cause-specific mortality among adolescents and adults in eastern and southern Africa., Methods: In this surveillance study, we harmonised verbal autopsy and residency data from nine health and demographic surveillance system (HDSS) sites in Kenya, Malawi, Tanzania, South Africa, Uganda, and Zimbabwe, each with variable coverage from Jan 1, 1995, to Dec 31, 2019. We included all deaths to adolescents and adults aged 12 or over that were residents of the study sites and had a verbal autopsy conducted. InSilicoVA, a probabilistic model, was used to assign cause of death on the basis of the signs and symptoms reported in the verbal autopsy. Levels and trends in all-cause and cause-specific mortality rates and cause-specific mortality fractions were calculated, stratified by HDSS site, sex, age, and calendar periods., Findings: 52 484 deaths and 5 157 802 person-years were reported among 1 071 913 individuals across the nine sites during the study period. 47 961 (91·4%) deaths had a verbal autopsy, of which 46 570 (97·1%) were assigned a cause of death. All-cause mortality generally decreased across the HDSS sites during this period, particularly for adults aged 20-59 years. In many of the HDSS sites, these decreases were driven by reductions in HIV and tuberculosis-related deaths. In 2010-14, the top causes of death were: road traffic accidents, HIV or tuberculosis, and meningitis or sepsis in adolescents (12-19 years); HIV or tuberculosis in adults aged 20-59 years; and neoplasms and cardiovascular disease in adults aged 60 years and older. There was greater between-HDSS and between-sex variation in causes of death for adolescents compared with adults., Interpretation: This study shows progress in reducing mortality across eastern and southern Africa but also highlights age, sex, within-HDSS, and between-HDSS differences in causes of adolescent and adult deaths. These findings highlight the importance of detailed local data to inform health needs to ensure continued improvements in survival., Funding: National Institute of Child Health and Human Development of the US National Institutes of Health., Competing Interests: Declaration of interests LM reports research grants from Wellcome Trust, the US National Institutes of Health (NIH), and Medical Research Council Centre for Global Infectious Disease Analysis funding from the UK Medical Research Council (MRC) and the UK Department for International Development. SG reports research grants from Wellcome Trust, NIH, Bill & Melinda Gates Foundation, and WHO; financial support for attending meetings and travel from Imperial College London; and participation on a Data Safety Monitoring Board at Kings College London and as a board member at Biomedical Research Training Institute, Harare, Zimbabwe. CC reports research grants from NIH. SJC reports research grants from NIH; and acting as a paid consultant on verbal autopsy implementation methods and software for two non-governmental organisations (Vital Strategies and CDC Foundation). All other authors declare no competing interests. LM, CN, and SG have received funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK MRC and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC and FCDO Concordat agreement and this centre is also part of the European and Developing Countries Clinical Trials Partnership programme supported by the EU; and LM, CN, and SG have received funding by Community Jameel., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)