<i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> can cause fatal invasive infections, especially in immunocompromised patients. However, few antifungal drugs are available to help treat cryptococcosis. In this study, by compound library screening, we presented the first report of hit compound <b>P163-0892</b>, which had potent <i>in vitro</i> and <i>in vivo</i> antifungal activity against <i>Cryptococcus</i> spp. <i>In vitro</i> tests showed that <b>P163-0892</b> was not cytotoxic and had highly selective and strong antifungal activities against <i>Cryptococcus</i> spp. with MIC values less than 1 μg/mL. Synergism of <b>P163-0892</b> and fluconazole was also observed <i>in vitro</i>. The <i>in vivo</i> antifungal efficacy of <b>P163-0892</b> was assessed in a wax moth larval fungal infection model, and treatment with 10 mg/kg <b>P163-0892</b> caused a significant reduction in fungal burden and significant extension of the survival time. Taken together, our data indicate that the hit compound <b>P163-0892</b> warrants further investigation as a novel anti-<i>Cryptococcus</i> agent.