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<div><p><i>Clostridioides difficile</i> is a major cause of nosocomial infections, often associated with individuals who have gut dysbiosis from previous antibiotic therapies. <i>C</i>. <i>difficile</i> infections (CDI) have a high recurrence rate and impose significant financial and mortality burdens on the healthcare system. Therefore, novel anti-<i>C</i>. <i>difficile</i> drugs are urgently needed to treat and reduce the severity and recurrence of infection. In this study, we screened a library of 618 antiviral drugs to identify a potential candidate for repurposing as novel anti-<i>C</i>. <i>difficile</i> therapeutics. Following our preliminary screening, we identified 9 novel compounds that inhibited <i>C</i>. <i>difficile</i> at a concentration of 16 μM or lower. Among these, 4 antiviral compounds demonstrated the most potent anti-<i>C</i>. <i>difficile</i> activity against a panel of 15 <i>C</i>. <i>difficile</i> isolates, with minimum inhibitory concentrations (MICs) comparable to the drug of choice, vancomycin. These include rottlerin (MIC<sub>50</sub> = 0.25 μg/mL), α-mangostin (MIC<sub>50</sub> = 1 μg/mL), dryocrassin ABBA (MIC<sub>50</sub> = 1 μg/mL), and obefazimod (MIC<sub>50</sub> = 4 μg/mL). All exhibited minimal to no activity against representative members of the human gut microbiota. Interestingly, α-mangostin, a natural xanthone derived from the mangosteen fruit, exhibited strong bactericidal action, clearing a high inoculum of <i>C</i>. <i>difficile</i> in less than an hour. All other drugs exhibited bacteriostatic activity. Given their characteristics, these compounds show great promise as novel treatments for CDI.</p></div>