Enterovirus type 71 (EV71) infection usually causes hand, foot and mouth disease (HFMD) in infants and young children. Severe EV71 infections can result in central nervous system complications, and even death. Previous studies suggest that EV71-induced severe complications are associated with programmed cell death and production of pro-inflammatory factors. To determine the molecular morphology and characteristics of EV71-induced cell death, EV71-infected cells were subjected to morphological analysis, JC-1 staining for potential of mitochondrial membrane, fluorescence-activated cell sorting, Annexin V-FITC/PI double staining, and lactate dehydrogenase (LDH) release assay. Western blotting was used to identify the activation of programmed cell death factors, including poly (ADP-ribose) polymerase (PARP), caspase-9, caspase-3, Gasdermin D, and MLKL. The results showed that EV71-infected cells mainly induced apoptotic cell death with a small portion of cellular necrosis. The cleavage of PARP, caspase-9, caspase-3 was observed. Although cell death was mostly inhibited by a caspase inhibitor, cell death still could be observed during the early stage of virus infection. The results suggest that EV71 infection mainly induces apoptotic cell death in combination with a caspase-independent cell programmed death.