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Background: <i>Clostridioides difficile</i>-associated disease (CDAD) is a major healthcare-associated infection. New treatment options for CDAD are needed. A traditional Chinese medicinal formula, Huo Xiang Zheng Qi (HXZQ), was chosen to test against CDAD in a mouse model. Methods: C57BL/6 mice were challenged with <i>C difficile</i> (ATCC 43255) orally; then received saline; vancomycin 25 mg/kg; or HXZQ in two different concentrations twice daily for 5 days. The animals’ body weight; clinical signs; and survival rates were registered daily. Fecal pellets from each animal were taken for PCR analysis as a control of infection. Results: 50% of the mice receiving saline died; 85.7% of the mice receiving vancomycin survived; 75% of the mice receiving HXZQ survived; and 87.5% of the mice receiving a 1:1 saline dilution of HXZQ survived. The HXZQ-treated groups were <i>C. difficile</i> PCR positive with loads less than that of the untreated mice. The weight loss in the vancomycin plus HXZQ 1:1 treated group; the vancomycin-treated group; and the untreated group were 3.08%, 4.06%, and 9.62%, respectively. Conclusions: our results showed that HXZQ can protect mice from CDAD-related death as effectively as vancomycin and the combination of vancomycin and HXZQ may give even better protection.