Benzodiazepine (BZD) therapy has been associated with several side effects in hospitalized patients. We developed a protocol-based pharmacotherapy management (PBPM) to recommend BZD discontinuation for patients at high risk for postoperative delirium (PD) following cardiovascular surgery. This study investigated whether implementing PBPM affects BZD prescription trends among cardiovascular surgeons for PD non-high-risk patients. This single-center retrospective cohort study collected all prescription orders of BZD from June 1, 2018, to May 31, 2023, and these orders were divided into 2 periods: 2 years and 6 months before and after PBPM. Changes in BZD prescription trends for patients with non-high-risk of PD were analyzed using interrupted time series (ITS). Furthermore, all patients in the department of cardiovascular surgery were also investigated as supplementary analysis. ITS analysis revealed that there was a significant level change in BZD prescriptions (-20%, 95% confidence interval: -37 to -2.8, p = 0.023), and the slope exhibited a downward trend (-0.90%, 95% confidence interval: -1.9 to 0.07, p = 0.068) in PD non-high-risk patients. In all patients, the level change was -21% (95% confidence interval: -0.36 to -0.9, p = 0.004) and the slope change was -0.85% (95% confidence interval: -1.7 to -0.02, p = 0.045). These results suggest that PBPM implementation significantly reduced the BZD prescription rate among cardiovascular surgeons for patients with a non-high-risk of PD. The alteration in prescription trends might be attributed to pharmacist interventions targeting patients with a high risk of PD, which influenced the prescribing behavior of cardiovascular surgeons.