Objective: To estimate the pooled prevalence and identify determinants of Rhesus isoimmunization among pregnant women in African hospitals. Methods: We conducted a systematic review following PRISMA guidelines, searching PubMed, SCOPUS, Web of Science, Lens.org, and Google Scholar for observational studies (2010–May 2025) on Rhesus isoimmunization in African hospital settings. The PICO framework guided the research question (Population: pregnant women; Intervention: none; Comparison: subgroups; Outcome: prevalence and determinants). Data were extracted using a standardized form, and study quality was assessed with the Joanna Briggs Institute checklist. A random-effects model with logit transformation pooled prevalence estimates. Heterogeneity was evaluated using I 2 and Cochran’s Q, and publication bias was assessed via Fail-Safe N, Kendall’s Tau, Egger’s regression, and funnel plots. Results: Nine studies (n=28,188 women) from Nigeria, Ethiopia, Uganda, and DR Congo showed a pooled prevalence of 2.93% (95% CI: 1.58%–5.36%), with high heterogeneity (I 2=85.12%, Q=48.320, p<0.001). Regional prevalence ranged from 0.31% (DR Congo) to 7.04% (Ethiopia). Key determinants included previous pregnancies, abortions, stillbirths, blood transfusions, and lack of anti-D prophylaxis. No publication bias was detected (Fail-Safe N=2,581, Egger’s p=0.672). Conclusions: Rhesus isoimmunization affects ~2.93% of pregnant women in African hospitals, posing a significant risk of hemolytic disease of the fetus and newborn. Routine Rhesus screening, accessible anti-D prophylaxis, and policy reforms are critical to reduce maternal and neonatal morbidity.