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Abstract Background Mpox remains a significant public health threat in Africa, with recent outbreaks driven by newly emergent clades I and II. Vaccination is a critical intervention for outbreak control, yet evidence on vaccine acceptance and uptake across the continent has not been comprehensively synthesized. This study aimed to determine the pooled prevalence and determinants of mpox vaccine acceptance and uptake in Africa. Methods We conducted a systematic review and meta-analysis following PRISMA guidelines, registered with PROSPERO (CRD420251126033). We searched PubMed, Scopus, Web of Science, CINAHL, ScienceDirect, and African Journals Online from 1970 to August 2025. Data were extracted using a standardized form, and quality was assessed with Joanna Briggs Institute tools. Pooled estimates were calculated using random-effects generalized linear mixed models with Probit-Logit transformation. Subgroup analyses and meta-regressions explored heterogeneity by region, population, setting, and time period. Results Of 9,748 records screened, 35 studies were included. The overall mpox vaccine acceptance rate was 53.55% (95% CI: 46.16–60.79), with high heterogeneity (I 2 =98%). Central Africa showed moderate acceptance at 54.17% (95% CI: 20.82–84.16), Eastern Africa at 54.16% (95% CI: 42.43– 65.44), while Western Africa was lower at 50.11% (95% CI: 39.94–60.27). Acceptance was highest in Southern Africa (67.43%; 95% CI: 61.85–72.67). Healthcare workers’ acceptance was 51.63% (95% CI: 39.37–63.70) and medical students’ was 46.17% (95% CI: 38.53–54.01), both lower than the general population (62.46%; 95% CI: 52.25–71.66). Actual vaccine uptake was 20.94% (95% CI: 10.06–38.56), varying significantly by country, with the Democratic Republic of the Congo at 20.01% (95% CI: 7.45–43.75). A significant decline occurred after 2022 (pre-2022: 36.0% [95% CI: 19.74–56.26]; post-2022: 3.4% [95% CI: 0.56–17.96]). Key determinants of acceptance included higher mpox knowledge, trust in health authorities, prior vaccination history, and free vaccine access. Conclusion There is a substantial gap between mpox vaccine acceptance and actual uptake in Africa, with a significant decline in coverage since 2022. Strategies to enhance vaccination must address both demand and supply challenges, including equitable distribution and integration into routine immunization systems. These findings underscore the need for context-specific, multi-level interventions to translate willingness into actual vaccine uptake.