AIM: Clinical practice guidelines (CPGs) have progressively become a popular tool for making optimal clinical decisions. The literature shows that the poor quality of CPGs can form a barrier against adhering to them, resulting in a suboptimal level of healthcare. The objective of this systematic review is to evaluate the quality of CPGs in the Middle East and North Africa (MENA) region using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) Instrument. METHODS: The authors searched in the MEDLINE and EMBASE databases through the Ovid interface on May 25, 2019. Keywords relating to CPGs and MENA countries were combined using Boolean search operators. The search was not limited to specific diseases. The quality of guidelines was appraised by two reviewers independently using the AGREE II Instrument. Discrepancies within a group were resolved through the involvement of a principle investigator. RESULTS: A total of 61 CPGs were appraised. These guidelines were mainly from Saudi Arabia, and the most covered disease topic was cancer. Among the six domains of the AGREE II Instrument, CPGs scored the highest on clarity of presentation (mean 82%), while the lowest score was granted to the rigor of development domain (mean 28%). This indicates substantial deficiencies in reporting the developmental processes of CPGs and the resources used for the synthesis of evidence. CONCLUSION: From this review, it was found that the number of retrieved guidelines published in the MENA region is limited considering the large geographical area of the MENA region. The main domains that have higher quality scores were clarity of presentation and scope and purpose, whereas domains with the lowest scores were rigor of development and applicability. The authors' findings will help policymakers identify areas for improvement in CPGs, which can lead them to implement strategies such as the training of individuals and recruitment of international experts to ultimately develop high-quality CPGs.