Enterovirus 71 (EV71) infection mainly causes hand, foot, and mouth disease (HFMD) and remains a serious public health problem to the children under the age of 5. Until now, there is no specific drug to treat HFMD in clinical and there is an urgent to explore the new target and the new drug to address clinical challenges. At present, we found histone deacetylase 11 (HDAC11) involves in supporting EV71 replication. We also used HDAC11 siRNA and an HDAC11 inhibitor FT895 to downregulate HDAC11 expression and found that targeting HDAC11 could significantly restrict EV71 replication in vitro and in vivo. Our results revealed the new role of HDAC11 participating in EV71 replication and broadened our knowledge regarding the functions of HDAC11 and the roles of HDACs in the epigenetic regulation of viral infectious diseases. Our results for the first time identified FT895 as an effective inhibitor of EV71 in vitro and in vivo, which may contribute to be a potential drug to treat HFMD.