Genipin is an iridoid compound and an aglucon of geniposide isolated from Gardenia fructus. We have previously reported that genipin induces neurite outgrowth in PC12h and Neuro2a cells and protects against cytotoxicity induced by several conditions such as β-amyloid peptide, serum deprivation, and oxidative stress in rat primary hippocampal neurons and Neuro2a cells. In this paper, we examined the protective effect of genipin on A23187 (a calcium ionophore)-induced cytotoxicity in Neuro2a cells. A23187 induced cytotoxicity in concentration- and time-dependent manners as assayed by measurements of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetazolium bromide (MTT) reduction activity and lactate dehydrogenase (LDH) release. The cytotoxicity was significantly suppressed by genipin in a concentration-dependent manner. A23187 also significantly activated caspase3/7, which is known to be the critical mediator of apoptosis, after 1 h, and the cytotoxicity was clearly blocked by an inhibitor of caspase 3/7. Furthermore, A23187 induced the expression of immunoglobulin-binding protein/glucose-regulated protein of 78 kDa (BiP/GRP78) protein, which is an endoplasmic reticulum (ER) stress marker protein, and the expression was suppressed by genipin. These results suggest that genipin protects Neuro2a cells from A23187-induced cytotoxicity mediated by caspase 3/7 and ER stress. Therefore, genipin may be effective in preventing neurodegeneration observed in Alzheimer's disease and Parkinson's disease involving ER stress.