Pre-exposure prophylaxis (PrEP) has emerged as a crucial tool in HIV prevention globally, yet its implementation in the Middle East and North Africa (MENA) region faces unique challenges. PrEP is expected to be effective in reducing HIV transmission. However, there is limited comprehensive data about its awareness, utilization, and effectiveness within MENA countries. The region's distinct cultural, social, and healthcare system characteristics create specific barriers that must be addressed. This study aims to evaluate PrEP's value and effectiveness and to develop targeted recommendations for overcoming barriers and expanding PrEP programs to better serve the region's specific needs and populations at risk. We searched PubMed, Scopus, and Web of Science databases through October 2024, using keywords related to HIV, PrEP, and the MENA region. Eligible studies included peer-reviewed clinical research on PrEP use in MENA countries, focusing on high-risk populations. Two independent reviewers screened titles, abstracts, and full texts using the Rayyan software, with disagreements resolved by a senior reviewer. Studies across the MENA region showed varying levels of PrEP awareness and willingness to use, with MSM communities showing higher interest. While PrEP proved effective for HIV prevention when properly used, implementation faced barriers, including costs, stigma, and accessibility. Despite the potential of PrEP implementation in HIV prevention, its efficacy in the MENA region remains unproven due to a lack of clinical studies. Successful implementation of PrEP in this region requires addressing key challenges, including financial accessibility, awareness, stigma, and healthcare integration. Morocco's pilot program serves as a promising example, but broader adoption must focus on improving accessibility and affordability. Future efforts should tailor interventions to meet the needs of at-risk populations, with an emphasis on enhancing adherence and retention rates to ensure effectiveness in diverse MENA settings.