Vaccine hesitancy (VH) is the seventh among the WHO’s top 10 threats to global public health, which has continued to perpetuate the transmission of vaccine preventable diseases (VPDs) in Africa. Consequently, this paper systematically reviewed COVID-19 vaccine acceptance rates (VARs)—including the vaccine uptake and vaccination intention—in Africa from 2020 to 2022, compared the rates within the five African regions and determined the context-specific causes of VH in Africa. Generally, COVID-19 VARs ranged from 21.0% to 97.9% and 8.2% to 92.0% with mean rates of 59.8 ± 3.8% and 58.0 ± 2.4% in 2021 and 2022, respectively. Southern and eastern African regions had the top two VARs of 83.5 ± 6.3% and 68.9 ± 6.6% in 2021, and 64.2 ± 4.6% and 61.2 ± 5.1% in 2022, respectively. Based on population types, healthcare workers had a marginal increase in their mean COVID-19 VARs from 55.5 ± 5.6% in 2021 to 60.8 ± 5.3% in 2022. In other populations, the mean VARs decreased from 62.7 ± 5.2% in 2021 to 54.5 ± 4% in 2022. As of 25 October 2022, Africa lags behind the world with only 24% full COVID-19 vaccinations compared to 84%, 79% and 63% reported, respectively, in the Australian continent, upper-middle-income countries and globally. Apart from the problems of confidence, complacency, convenience, communications and context, the context-specific factors driving COVID-19 VH in Africa are global COVID-19 vaccine inequality, lack of vaccine production/maintenance facilities, insecurity, high illiteracy level, endemic corruption, mistrust in some political leaders, the spreading of unconfirmed anti-vaccination rumors and political instability. With an overall mean COVID-19 acceptance rate of 58%, VH still subsists in Africa. The low VARs in Africa have detrimental global public health implications, as it could facilitate the emergence of immune invading SARS-CoV-2 variants of concern, which may spread globally. Consequently, there is a need to confront these challenges frontally and engage traditional and religious leaders in the fight against VH in Africa, to restore public trust in the safety and efficacy of vaccines generally. As the availability of COVID-19 vaccines improves, the vaccination of pets and zoo-animals from which reverse zoonotic transmission of SARS-CoV-2 have been reported is recommended, to limit the evolution and spread of new variants of concern and avert possible SARS-CoV-2 epizootic or panzootic diseases in susceptible animal species.