Despite accounting for a substantial proportion of the global population and disease burden, African countries are underrepresented in randomized controlled trials (RCTs), including those informing cardiovascular (CV) care. In this study, we sought to quantify African representation in RCTs published from 2019 to 2024 in: 1) 5 leading general medical journals; and 2) 3 leading CV journals. We conducted a systematic review of RCTs published from 2019 to 2024 in the British Medical Journal, the Journal of the American Medical Association, The Lancet, Nature Medicine, and the New England Journal of Medicine, and in Circulation, the European Heart Journal, and the Journal of the American College of Cardiology. Eligible studies included traditional, pragmatic, cluster, and stepped-wedge RCTs. African representation was assessed by trial scope (Africa-only vs multicontinental), country and regional participation, disease category, and African authorship. Among 2,138 RCTs published in leading general medical journals, only 83 (3.9%) were conducted exclusively in Africa, and 195 (9.1%) were multicontinental studies including at least 1 African site. In the CV journals, 2 out of 334 RCTs (0.6%) were conducted exclusively in Africa, and African sites were included in only 9 multicontinental trials (2.7%). South Africa accounted for the majority of Africa-based RCTs across both journal categories. Regionally, southern Africa predominated and central Africa was minimally represented. Trials published in general medical journals and conducted exclusively in Africa largely focused on infectious diseases (n = 63; 75.9%), with only 3 addressing cardiovascular disease (CVD). In contrast, Africa-including multicontinental trials more frequently investigated noncommunicable diseases, including CVD. African leadership was common in Africa-only trials but rare in multicontinental studies. African countries are profoundly underrepresented in RCTs published in the world's most influential medical and CV journals. Addressing this imbalance requires expanding African participation in global trials, investing in local research capacity, and promoting equitable leadership to strengthen the relevance and validity of clinical evidence. (Underrepresentation of African Countries in Randomized Controlled Trials: A Systematic Review of Leading General Medical and Cardiovascular Journals; CRD42024603157).