Background The prevalence and characteristics of inappropriate use of proton pump inhibitors (PPIs) to prevent stress-related mucosal disease (SRMD) during the perioperative period and its associated factors are rarely reported. This study aimed to investigate the prevalence and characteristics of inappropriate prophylactic use of proton pump inhibitors (PPIs) during the perioperative period and identify its associated factors in a tertiary care and academic teaching hospital in China and to provide evidence for regulation authorities and pharmacists to take targeted measures to promote rational drug use. Methods Inpatients who underwent surgical operations and received prophylactic use of PPIs from June 2022 to November 2022 were included in this retrospective study. The appropriateness of perioperative prophylactic use of PPIs was evaluated by clinical pharmacists. Associated factors with inappropriate perioperative prophylactic use of PPIs were analyzed by univariable and multivariable logistic regression. Results Four-hundred seventy-two patients were finally included in this study, of which 131 (27.75%) patients had at least one problem with inappropriate perioperative prophylactic use of PPIs. The three most common problems were drug use without indication (52.0%), inappropriate usage and dosage (34.6%), and inappropriate duration of medication (6.7%). Multiple logistic regression analysis showed that oral dosage form of PPIs [OR = 18.301, 95% CI (7.497, 44.671), p < 0.001], discharge medication of PPIs [OR = 11.739, 95% CI (1.289, 106.886), p = 0.029], and junior doctors [OR = 9.167, 95% CI (3.459, 24.299), p < 0.001] were associated with more inappropriate prophylactic use of PPIs. Antithrombotics [OR = 0.313, 95% CI (0.136, 0.721), p = 0.006] and prolonged postoperative hospital stay (longer than 15 days) [OR = 0.262, 95% CI (0.072, 0.951), p = 0.042] were associated with less inappropriate prophylactic use of PPIs. Conclusions The inappropriate prophylactic use of PPIs during the perioperative period is common. Regulation authorities and pharmacists should take more targeted measures to promote the rational prophylactic use of PPIs during the perioperative period.