Porcine epidemic diarrhea virus (PEDV), a member of the Coronaviridae family, causes acute diarrhea, vomiting, dehydration, and high mortality rates in neonatal piglets. Severe outbreaks of PEDV variants have re-emerged in Asia and North America since 2010, causing tremendous economic losses to the swine industry. The lack of effective therapeutic treatment promotes the research for new antivirals. Lithium chloride (LiCl) has been reported as a potential antiviral drug for certain viruses. In this study, the antiviral effect of LiCl on PEDV in Vero cells was evaluated. Real-time quantitative PCR and indirect immunofluorescence assay indicated that LiCl effectively inhibited the entry and replication of PEDV in Vero cells. The expression of viral RNA and protein of PEDV in Vero cells was suppressed in a dose-dependent manner by LiCl. Moreover, addition of LiCl inhibited both early and late cell apoptosis induced by PEDV. Our data implied that LiCl could be a potential antiviral drug against PEDV infection. Further studies are required to explore the antiviral effect of lithium chloride on PEDV infection in vivo.