Objective: To assess the in-hospital mortality from acute stroke and its predictors in sub-Saharan Africa. Method: The literature search was conducted in the databases of PubMed/Medline, Embase, CINAHL, and Google Scholar. The retrieved studies were screened by titles and abstracts, and then full texts were assessed for eligibility. The methodological quality of the included studies was assessed using the Joanna Briggs Institute’s critical appraisal checklist. The publication bias was assessed using the funnel plot asymmetry and the Egger tests. Data were analyzed using Stata software version 15.0 in a random-effect model. Result: A total of 27 studies with a total sample size of 6331 were included in this systematic review and meta-analysis. The pooled estimated prevalence of in-hospital mortality due to stroke was 22% (95% confidence interval = 0.17–0.27). Stroke mortality in Western Africa (37%, 95% confidence interval = 0.24–0.50) was higher than in Eastern Africa (15%, 95% confidence interval = 0.12–0.19) and Southern Africa (18%, 95% confidence interval = 0.06–0.19). In three studies, mortality was higher in hemorrhagic stroke (25%) than ischemic stroke (14%). Risk factors associated with higher mortality were admission Glasgow Coma Scale, stroke severity, age, sex, presence of hypertension, and declined renal function. Conclusion: The in-patient mortality of stroke in sub-Saharan Africa was high. Therefore, there is an urgent need for further stroke epidemiology studies in stroke subtypes and the performance of patient-level meta-analysis to understand the risk factors associated with mortality and herald appropriate intervention to curb the high mortality rate in the region.