Background Depression is among the most common mental health disorders affecting social and academic progress of university students globally. However, the variations in prevalence reported by different published studies leaves the true burden of depression among medical students in Africa unknown. Objectives This study aimed at conducting a systematic review and meta-analysis to report the true estimate of prevalence of depression among medical students in Africa between 2012 and 2022. Methods Articles that reported prevalence of depression among medical students in Africa between 2012 and 2022 study period were searched for in PubMed, Google Scholar, African Journals Online, and Embase. Two investigators independently extracted the data for full review and eligible studies were considered for analysis after a consensus, quality of articles was assessed using JBI Critical Appraisal tool [1] for prevalence studies. R version 4.3.2 [2] was used to establish the pooled prevalence using a random effects model, funnel plot and Eggers test were used to check for publication bias. Results A total of twenty-six cross-sectional studies involving 11386 (Females: 6070, 53.3%) medical students, mean age 23, were included in this study. PHQ9 (n=10), DASS21 (n=7), BDI-II (n=5) were the most used screening instruments. The overall pooled prevalence of depression was 38% (p < 0.00). Sub-group analysis by instrument used i.e. DASS21, PHQ-9, BDI-II, revealed prevalence of 50% (p < 0.01), 39% (p < 0.01) and 32% (p < 0.01) respectively. Conclusion Nearly two-fifths of medical students in Africa suffer from depression. The findings emphasize the urgent need for research into the causes, alongside early diagnosis with standardized tools and targeted interventions to manage depression effectively among this demographic. PROPERO (CRD42022372866).