Despite the crucial role the COVID-19 vaccine played in curbing the pandemic, a significant portion of Black and African American individuals expressed hesitancy toward being vaccinated. This review aimed to identify the determinants of COVID-19 vaccine hesitancy among Black and African American individuals in the U.S. The literature search was conducted in December 2022 according to the PRISMA criteria focusing on empirical studies. Data extraction methods, critical appraisal, and secondary thematic analysis were conducted on both quantitative and qualitative studies. Sixteen quantitative studies identified the key factors associated with vaccine hesitancy, such as confidence in vaccine effectiveness, safety, and trust in the healthcare system. Fourteen qualitative studies revealed major themes of mistrust, fear, and information needs, including historical mistrust, concerns about the vaccine development process, and contemporary institutional mistrust. The synthesis of quantitative and qualitative findings derived from this review provides a nuanced understanding of the determinants of vaccine hesitancy in Black and African American communities in the U.S., offering a foundation for the development of evidence-based interventions. Mistrust in the healthcare system, fear, and informational gaps on vaccine safety and effectiveness were identified as significant barriers to vaccination, demanding targeted interventions.