Introduction: The rate of awareness of prospective prescription review for inpatient prescriptions remains low, and no study has evaluated prospective prescription review systems among hospitalized patients. In this study we evaluate the effect of a prospective prescription review system on the use of analgesics, clinical outcomes, and medical costs in hospitalized patients who underwent surgery. Methods: A single-center, real-world study was conducted retrospectively at Drum Tower Hospital, Nanjing, China. Patient data were extracted from the medical records, before (June 2016–May 2017) and after (June 2018–May 2019) prescription review system implementation. The primary outcome was proportion of prescriptions of analgesics with potential risks. The secondary outcomes included prescription of opioids or non-opioids, usage of medications to manage analgesics-related adverse events, clinical outcomes, and medical costs. Propensity score matching was used to balance the cohort of patients before and after implementation of the prescription review system. Results: A total of 28,150 inpatients were included for study analysis. After implementation of the prescription review system, the proportion of prescriptions of analgesics with potential risk was significantly reduced (6.3% vs 26.1%, P < 0.05). A significant decrease was observed in the proportion of patients prescribed opioids (24.3% vs 27.5%, P < 0.001) and tramadol (4.7% vs 12.1%, P < 0.001). There was a significant decrease in prescription of antiemetics (21.8% vs 34.1%, P < 0.001) and cathartics (38.4% vs 50.6%, P < 0.001) which were used in the management of opioid-related adverse events. There was a decreased length of stay in hospital [median (Q1, Q3) 10 (6, 17) vs 11 (7, 18), P < 0.01)] with similar readmission rates within 30 days post discharge (1.0% vs 0.8%, P = 0.099). Conclusions: The introduction of the prescription review system was associated with safer prescribing, including a reduction in prescriptions of analgesics with potential risk and necessity of medication to manage analgesics-related adverse events, which resulted in better clinical outcomes and cost saving.