Background: Globally, one-third of pregnant women are at risk of iron deficiency, particularly in the African region. While recent findings show that iron and folate supplementation can lower the risk of adverse birth outcomes and childhood mortality, our understanding of its impact in Africa remains incomplete due to insufficient evidence. This protocol outlines the systematic review steps to investigate the impact of oral iron and folate supplementation during pregnancy on adverse birth outcomes, neonatal mortality and infant mortality in Africa. Methods and analysis: MEDLINE, PsycINFO, Embase, Scopus, CINAHL, Web of Science, and Cochrane databases were searched for published articles. Google Scholar and Advanced Google Search were used for gray literature and nonindexed articles. Oral iron and/or folate supplementation during pregnancy is the primary exposure. The review will focus on adverse birth outcomes, neonatal mortality and infant mortality. Both Cochrane Effective Practice and Organization of Care and Newcastle-Ottawa Scale risk of bias assessment tools will be used. Meta-analysis will be conducted if design and data analysis methodologies permit. This systematic review and meta-analysis will provide up-to-date evidence about iron and folate supplementation's role in adverse birth outcomes, neonatal mortality and infant mortality in the African region. Ethics and dissemination: This review will provide insights that help policymakers, program planners, researchers, and public health practitioners interested in working in the region. PROSPERO registration number: CRD42023452588.