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Clostridioides difficile infection (CDI), recurrently reported as an urgent threat owing to its increased prevalence and mortality, has attracted significant attention. As the use of antibiotics to treat CDI has many limitations, such as high recurrence rate, the need to actively seek and develop other drugs that can effectively treat CDI with fewer side effects has become a key issue in CDI prevention and treatment. This study aimed to evaluate the inhibitory effect of Galla chinensis (GC) and its main component, tannic acid (TA), against C. difficile in vitro and its therapeutic effect on CDI in vivo . When GC and TA concentrations were 250 and 64 mg/L, respectively, the cumulative antibacterial rate against C. difficile reached 100%. The sub-MIC of TA significantly inhibited C. difficile sporulation, toxin production, and biofilm formation in vitro . Compared with the CDI control group, TA-treated mice lost less weight and presented a significantly improved survival rate. TA significantly reduced the number of spores in feces, decreased serum TcdA level, and increased serum interleukin 10 (IL-10). Based on the inhibitory effect of TA on C. difficile in vitro and its therapeutic effect on the CDI mouse model, we consider TA as a potentially effective drug for treating CDI. IMPORTANCE Clostridioides difficile is one of the major pathogens to cause antibiotic-associated diarrhea. Although antibiotic treatment is still the most commonly used and effective treatment for CDI, the destruction of indigenous intestinal microbiota by antibiotics is the main reason for the high CDI recurrence rate of about 20%, which is increasing every year. Moreover, the growing problem of drug resistance has also become a major hidden danger in antibiotic treatment. GC has been used to treat diarrhea in traditional Chinese medicine. In the present study, we evaluated the inhibitory effect of TA, the main component of GC, on dissemination and pathogenic physiological functions of C. difficile in vitro , as well as its therapeutic efficacy in a CDI model. Overall, TA is considered to be a potentially effective drug for CDI treatment.