Purpose <p>Multimorbidity and polypharmacy are increasingly prevalent in the older population and are associated with a higher risk of potentially inappropriate medications (PIM), drug–drug interactions (DDI), and adverse drug reactions (ADR). Although medication review (MR) and deprescribing are effective strategies, their manual implementation can be complex, time-consuming, and prone to clinical variability. Clinical Decision Support Systems (CDSS) offer advanced digital solutions to optimize polypharmacy by analyzing multidimensional clinical data and generating personalized recommendations.</p> Methods <p>A narrative review was conducted to identify and compare the main CDSS developed for the polypharmacy management, MR and deprescribing in older adults and patients with multimorbidity. Systems were classified as manual, hybrid, or automated according to their data acquisition modalities. Operational characteristics, integration into clinical workflows, decision-support functions, generated outputs, and available validation evidence across different healthcare settings were assessed. Owing to the narrative nature of the review and the heterogeneity of the included evidence, no formal risk-of-bias assessment or certainty-of-evidence evaluation was performed.</p> Results <p>Manual CDSS require direct data entry by clinicians and are associated with a high operational burden. Hybrid systems combine automatic data acquisition with manual integration, balancing efficiency and clinical oversight. Automated systems, integrated into electronic health records (EHR), provide real-time decision support with minimal human intervention. Considerable heterogeneity was observed across identified platforms in terms of automation, implementation characteristics, and stage of validation, with evidence ranging from development and feasibility studies to observational analyses and randomized controlled trials (RCT).</p> Conclusion <p>CDSS represent promising tools for safer and more effective management of polypharmacy in complex patients. Advanced integration into clinical workflows and systematic use of multidimensional data may enhance their impact. However, the heterogeneity of available systems and the variability in their level of clinical validation highlight the need for comparative studies, pragmatic trials, and real-world implementation evaluations. Such studies are necessary to clarify the impact of different CDSS models on prescribing appropriateness, medication-related risks, patient outcomes, and long-term sustainability within routine healthcare settings.</p>