The aim of the present study was to examine the protective effects and mechanism of sika deer (Cervus nippon Temminck) velvet antler polypeptides (VAPs) against MPP+ exposure in the SH-SY5Y human neuroblastoma cell line. MPP+ cytotoxicity and the protective effects of VAPs on the SH-SY5Y cells were determined using an MTT assay. Cell apoptosis and mitochondrial membrane potential were detected using Hoechst 33342 and Rhodamine123 staining, respectively. Endoplasmic reticulum (ER) stress-related reactive oxygen species (ROS) production in the SH-SY5Y cells was detected using 2',7'-dichlorodihydrofluorescein diacetate fluorescent probes. The expression levels of proteins, including caspase-12, glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected using western blot analysis. The results showed that the half inhibitory concentration of MPP+ at 72 h was 120.9 mu mol/l, and that 62.5, 125, and 250 mu g/ml concentrations of VAPs protected the SH-SY5Y cells under MPP+ exposure. When exposed to 120.9 mu mol/l MPP+, changes in cell nucleus morphology, mitochondrial membrane potential and intracellular ROS were observed. VAPs at concentrations of 62.5, 125, 250 mu g/ml reduced this damage. Western blot analysis showed that protein expression levels of caspase-12, GRP78 and p-JNK were upregulated in the SH-SY5Y cells exposed to 120.9 mu mol/l MPP+ for 72 h. In addition, 62.5, 125, and 250 mu g/ml VAPs downregulated the expression levels of caspase-12 and p-JNK in a concentration-dependent manner, particularly the p-JNK pathway. The effects of VAPs on GRP78 and CHOP were weak. In conclusion, MPP+-induced SH-SY5Y cell death may be linked to ER stress. VAPs prevented MPP+-induced SH-SY5Y cell death by affecting the p-JNK pathway and caspase-12-mediated apoptosis. These findings assist in understanding the mechanism underlying the protective effect of VAPs on neurons.