BACKGROUND: Economic evaluations through decision-analytical models have played a limited role in shaping healthcare resource optimisation and reimbursement decisions in the Middle East. OBJECTIVE: This review aims to systematically examine economic evaluation studies focusing on decision-analytical models of medicines in the Middle East, defining methodological characteristics and appraising the quality of the identified models. METHODS: A systematic review approach was employed to identify published decision-analytical models of medicines in the Middle East. Six databases were searched (MEDLINE, EMBASE, Econlit, Web of Science, Global Health Cost-Effectiveness Analysis Registry and the Global Index Medicus) from 1998 to July 2024. Studies meeting the inclusion criteria-full economic evaluations of medicines using decision-analytical models in the Middle East-were considered. Data were extracted and tabulated to include study characteristics and methodological specifications, and data were narratively analysed. The Philips checklist was used to assess the quality of studies. RESULTS: Sixty-three decision-analytical modelling studies of medicines were identified and reviewed, from eight Middle Eastern countries, with the majority (90%) conducted in Iran, Saudi Arabia, Qatar and Egypt. The cost-effectiveness of medications for non-communicable diseases was explored in 77% of the models. Gross domestic product-based cost-effectiveness thresholds were commonly used, and international sources provided data on intervention effectiveness and health outcomes, while national sources were mainly used for the costs of resource use. Most models incorporated an assessment of parameter uncertainty, whereas other types of uncertainty were not explored. Studies from high-income countries were generally of higher quality than those from middle-income countries. CONCLUSIONS: The number of published decision-analytical models in the Middle East was low, considering the available medicinal products and disease burden. Key elements related to the quality of decision-analytical models, including analysis of the model structure, appropriateness of model inputs and uncertainty assessment, were not consistently fulfilled. Recommendations are provided to enhance the quality of future economic evaluation studies. This includes strengthening the existing health economics capacities, establishing country-specific health technology assessment systems (where possible), and initiating collaborations to generate national cost and outcome data. PROSPERO registration: CRD42021283904.