Background/Objective. Overprescribing proton-pump inhibitors (PPIs) has become the norm worldwide and represents a global health issue with tangible clinical and economic consequences. At national level, we do not know how pharmacists are contributing to this issue. Thus, the study focused on analyzing drug-related problems (DRPs) pertaining to PPI prescriptions, detected during the medication order review process in French hospitals, and associated pharmacist interventions (PIs). Methods. The study was based on a retrospective analysis of pharmacist interventions for DRPs detected during the medication order review and documented into the French Act-IP© database over a 12-year period. DRPs and PIs were analyzed, and independent factors of physician acceptance were assessed via multiple logistic regression. Results. Out of the 620,620 PIs registered, 29,694 targeted a PPI (4.8%). PPI’s DRPs were mostly related to the prescription of a “drug not available at the hospital” (26.1%) and a “drug use without indication” (18.3%); PIs were mostly “drug switch” (35.9%) and “drug discontinuation” (26.1%). In all, 18,919 PIs were accepted by physicians (63.7%). Acceptance was significantly associated with patient age: less accepted for the 18–75 years group (OR = 0.59, 95 CI [0.46–0.76]), and the >75 years group (OR = 0.57, 95 CI [0.44–0.73]) vs. <18 years group; for the type of DRP, “drug use without indication” was the less accepted (OR = 0.73, 95 CI [0.63–0.85]); for the type of PI, “dose adjustment” was the less accepted (OR = 0.32, 95 CI [0.23–0.45]). Conclusion. Pharmacists contribute to preventing DRPs associated with PPI prescriptions during the medication order review process. Moreover, they often detect PPIs used without indication and they propose drug discontinuation, which contributes to the PPI deprescribing process. PIs should be further developed in the future to reduce PPI overprescription.