Background Depression is estimated to be the leading cause of disability in South Africa, yet data on depression prevalence and antidepressant use are inconsistent and fragmentary. We present a system dynamics modelling approach to integrate these data and assess trends and inequalities in depression prevalence and treatment access.Methods We developed a deterministic model of the South African population aged 15 and older, stratified by age, sex, HIV status/stage and susceptibility to depression. Individual transitions between depressed/healthy and treated/untreated states were simulated over time, from 1985. The model was calibrated to depression prevalence data from nine nationally representative household surveys (2002-2024) and ten smaller studies reporting prevalence of antidepressant use, using a Bayesian approach.Results The model estimated a slight decline in depression point prevalence over time, from 5.1% (95% CI: 4.5-5.6%) in 2002 to 4.5% (95% CI: 4.0-5.0%) in 2024, although with a transient rise in depression prevalence during the COVID-19 period. In 2024, depression prevalence was higher in women (5.3%, 95% CI: 4.7-5.9%) than men (3.6%, 95% CI: 3.2-4.0%), and highest at ages 60 and older. The lifetime prevalence of depression was 70.6% (95% CI: 67.8-73.6); alternative model settings with a more concentrated distribution of depression risk were inconsistent with longitudinal data. The proportion of adults using antidepressants increased from 1.0% (95% CI: 0.8-1.2%) in 2008 to 2.8% (95% CI: 2.2-3.4%) in 2024. In 2024, antidepressant use was 11.0% (95% CI: 8.8-13.5%) in the private sector, compared to only 0.9% (95% CI: 0.7-1.1%) in the rest of the population, and the ratio of new antidepressant initiations to new cases of depression was 0.12 nationally.Conclusion The prevalence of depression in South Africa has been relatively stable over the last two decades. Although antidepressant use has increased, overall use remains low, and substantial inequality remains in access to treatment in the public and private health sectors.Competing Interest StatementThe authors have declared no competing interest.Funding StatementLJ, IP, NL, MB and LF were funded by the National Institute for Health and Care Research (NIHR) on Development and evaluation of a targeted, integrated, coherent and people-centred approach to the management of Multiple Long-Term Conditions (MLTC-M) in South African primary healthcare (NIHR 201816) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. LJ, MT and AH were funded by the U.S. National Institutes of Health{\textquoteright}s National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Fogarty International Center (FIC) under Award Number U01AI069924.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study used openly available data from the South African National Income Dynamics Study (https://saldru.uct.ac.za/surveys/national-income-dynamics-study-nids).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors. https://saldru.uct.ac.za/surveys/national-income-dynamics-study-nids