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Since the declaration of coronavirus disease 2019 (COVID-19) as a pandemic, intensive measures were taken to mitigate its negative health, psychological, social, and economic impact. COVID-19 continues to pose serious threats globally, with vaccination as the central safe strategy to control the pandemic. However, COVID-19 vaccine hesitancy is a major concern, especially in the Middle East and North Africa (MENA). Concerns regarding vaccine safety, efficacy, and misinformation contribute to vaccine hesitancy. Addressing these concerns and providing accurate information is crucial for increasing COVID-19 vaccine acceptance and uptake in this region, where the coverage is low. Variable rates of COVID-19 vaccine hesitancy were found in the numerous studies conducted in the region. Complex factors contributed to vaccination hesitancy in the region including concerns about COVID-19 vaccine safety and efficacy, low trust in healthcare systems, complacency toward the risks of COVID-19, constraints hindering access to COVID-19 vaccination services, as well as the circulation of misinformation and conspiracy beliefs about COVID-19 and its vaccination. Effective approaches to address COVID-19 vaccine hesitancy in the MENA region rely on developing evidence-based communication strategies that are recommended to build trust in vaccination, highlight the disease risks, and counter COVID-19 vaccine-related misinformation. Ensuring COVID-19 vaccine affordability is also necessary besides the cautious consideration of implementing COVID-19 vaccine mandates. Based on the preceding discussion, this chapter aims to identify the common themes of COVID-19 vaccine hesitancy in the MENA region. In addition, the chapter highlights the importance of understanding the root causes of COVID-19 vaccination hesitancy and its associated determinants to develop effective strategies for promoting COVID-19 vaccine acceptance and uptake in the MENA region. To build community trust, promote community education and awareness, and counter misinformation for better COVID-19 vaccine coverage in the region, it is recommended to involve healthcare professionals and policymakers., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)