Piperacillin/tazobactam (PIPC/TAZ) and vancomycin (VCM) are frequently used in combination (PTV) to manage severe healthcare-associated infections, but are also associated with an increased risk of acute kidney injury (AKI). In 2019, Ogaki Municipal Hospital implemented pharmacist-led interventions aimed at reducing PTV use and mitigating AKI. This study evaluated the impact of these interventions on antibiotic safety and patient outcomes. This retrospective study included hospitalized patients treated with PTV between January 2010 and December 2023. Details of these pharmacist interventions were reviewed retrospectively. Patients were categorized into pre- and post-intervention periods. The primary outcomes reported were the duration of PTV therapy and the incidence of AKI. Multivariable regression analyses were performed to evaluate the association between the intervention, therapy duration, and AKI incidence. Mediation analysis was conducted to assess whether the reduction in PTV duration mediated the effect of the intervention on AKI incidence. As a result, AKI incidence decreased from 19.8% in the pre-intervention period to 7.7% in the post-intervention period (p=0.038). In the PTV cohort, multivariable models showed lower AKI risk in the post period [adjusted odds ratio (OR) 0.283; 95% confidence interval (CI) 0.086 to 0.803; p=0.024] and a shorter PTV duration (β=−2.011 d; 95% CI −3.459 to −0.563; p=0.007). In mediation analysis, the shortening of PTV duration partially mediated the AKI reduction (ACME p=0.016). In conclusion, pharmacist-led interventions effectively reduced PTV duration leading to a decrease in AKI incidence, highlighting the critical role of pharmacists in promoting antimicrobial stewardship and improving patient outcomes.