Enterovirus 71(EV71) is the main pathogen of the hand, foot, and mouth disease. It was firstly isolated from sputum specimens of infants with central nervous system diseases in California in 1969, and has been repeatedly reported in various parts of the world, especially in the Asia-Pacific region. EV71 3C protein is a 183 amino acid cysteine protease that can cleave most structural and non-structural proteins of EV71. Based on the analysis and understanding of EV71 3C protease, it is helpful to study and treat diseases caused by EV71 virus infection. The EV71 3C protease promotes virus replication by cleaving EV71 synthesis or host proteins. Moreover, EV71 3C protease inhibits the innate immune system and causes apoptosis. At present, in order to deal with the damage caused by the EV71, it is urgent to develop antiviral drugs targeting 3C protease. This review will focus on the structure, function, and mechanism of EV71 3C protease.