The hypothalamic-pituitary-adrenal (HPA) axis is critical to mediating the body's response to stress. Corticotropin releasing hormone (CRH) plays a central role in controlling the stress response and regulating the HPA axis. Recent findings support CRH participates in the stress-induced hippocampal neuron apoptosis, but the underlying mechanisms are not fully understood. Our present study demonstrates that CRH can independently decrease hippocampal neuron cell viability in vitro in a concentration- and time-dependent manner. CRH receptor 1 (CRHR1) is involved in CRH-induced neuron apoptosis. Endoplasmic reticulum (ER) stress response marker, glucose-regulated protein 78 (GRP78), either protein or mRNA, is significantly elevated after treatment of CRH, and decreased when co-treated with salubrinal, ER stress inhibitor. The ER stress associated proapoptotic transcription factor C/EBP homologous protein (CHOP) and cleavage of caspase-12 protein expression are also increased following CRH treatment. Furthermore, we investigate which ER stress cascades are affected by CRH. CRH activates inositol-requiring enzyme 1 (IRE1), apoptosis signal regulating kinase 1 (ASK1), and c-jun kinase (JNK). Neuron apoptotic rate, examined by flow cytometry, is increased when CRH treatment and attenuated by salubrinal, thioredoxin (ASK1 inhibitor) and SP600125 (JNK inhibitor). Therefore, current data indicate that ER stress, through activating the IRE1/ASK1/JNK cascade, plays an important role in CRH-induced neuron apoptosis.