Vaccination plays a crucial role in combating the global COVID-19 pandemic. Immunizing all healthcare workers (HCWs) is essential for increasing vaccine confidence and acceptance within the general population. Understanding the factors that hinder or facilitate vaccine uptake among HCWs is of utmost importance, considering they are among the first to be vaccinated. This review follows Arksey and O’Malley’s five-stage methodological framework. We searched PubMed, Web of Science, ProQuest, WorldCat Discovery, and Google Scholar for peer-reviewed articles published from 2020 to 2023. A descriptive analysis and narrative synthesis approach were employed to collect and synthesize data. Using the social-ecological model as a framework, the literature was categorized into themes at the intrapersonal, interpersonal, organizational, community, and policy levels. We reviewed a total of fifty-three published academic articles, with the majority of studies conducted in Ethiopia and Nigeria. The intention for vaccine uptake resulted in an unsatisfactory (52%) overall uptake rate among HCWs. Individual-level determinants associated with vaccine uptake included being male, middle-aged, being a physician, having a higher level of education, and having a chronic illness. This review identified significant barriers at each level, such as safety concerns, perceived scientific uncertainty, vaccine ineffectiveness, lack of trust in stakeholders, and religious beliefs. Additionally, we identified facilitators at each level, with the most common factors promoting intention to uptake being the desire to protect oneself and others and a high perceived susceptibility to contracting COVID-19. This review highlights the existence of significant barriers to vaccine uptake on the African continent. Given that HCWs play a crucial role in guiding the public’s vaccination decisions, it is imperative to prioritize education and training efforts about the safety and effectiveness of COVID-19 vaccines.