Display omitted The effects of gastric acid suppressors (GASs) on Clostridioides difficile infection remain controversial. Moreover, studies have shown that GASs are overused. This study was designed to evaluate the effects of GAS use on the risk of C. difficile-induced diarrhea (CDID) development and to investigate the appropriate use of GASs. In this observational case–control study, patients hospitalized between January 2010 and December 2016 who had diarrhea after 3 days of hospitalization were included. The study (n = 122) and control (n = 122) groups were matched according to the patients’ hospitalization dates and departments. No significant difference in CDID development was observed between the study and control groups. However, GAS use was excessive in the study and control groups (usage rates were 90.2% and 91.8%, respectively) (p > 0.05). Most proton pump inhibitors and histamine-2 receptor antagonists were used without an appropriate indication. Surprisingly, the use of nonsteroidal anti-inflammatory drugs for 7 days and longer showed a significant difference between the study and control groups (p < 0.05). Additionally, significant differences in enteral feeding, oral nutritional support products, carbapenem, penicillin, glycopeptide antibiotics, antifungals, hypoalbuminemia, and increased leukocyte levels were observed between the study and control groups (p < 0.05). A significant difference in CDID development was not detected. The use of non-steroidal anti-inflammatory drugs for 7 days and longer was a risk factor for CDID development. Additionally, an excessive inappropriate use of GASs was observed. Clinicians should be cautious of all these factors, which may increase the risk of CDID development.