Background Enterovirus 71 (EV71) is a major virus that causes hand-foot-mouth disease. In cases of infants and young children, EV71 infection has been associated with severe neurological disease and potentially fatal systemic complications. The sporadic outbreak worldwide is increasingly prevalent in the Asia-Pacific region, where it has become a major public health concern. Objective No specific antiviral drugs are currently approved for the treatment of EV71 infection. The purpose of this study is to comprehensively review the research progress of anti-EV71 drugs (synthetic small molecule inhibitors and nature drugs) in the past twenty years, and further to promote the research and development of antiviral drugs against enterovirus infection. Methods This study reviewed the drugs on anti EV71 in the past decades. The literature search in PubMed database was conducted for original studies and review articles on drugs against enterovirus 71. Related articles published in English were selected for study and discussion. Results As reviewed in this paper, bioactive molecules include receptor analogues, protease inhibitors, natural drugs derived from traditional chinese medicine or natural medicine. These bioactive molecules have shown significant effectiveness in inhibiting the entry and replication of EV71 in vitro and in vivo experiments. Conclusion This review demonstrated that the entry receptor of EV71 into host cells has been studied, and receptor drugs against enterovirus have been made some progress, but most receptor analogues have not been reported. Further research is needed in this area in the future. On the other hand, the protease inhibitors have always been a major aspect of anti-enterovirus research and can be developed as antiviral agents for clinical application. In terms of natural drugs, many monomers derived from traditional chinese medicine or natural medicine have good antiviral activity and little toxic and side effects on host cells, but in view of their multi-target properties, the mechanism of drug action needs to be further studied.