The heavy metal cadmium (Cd) is well known to be neurotoxic. Studies have shown that apoptosis plays an essential role in Cd-induced brain injury; however, the mechanisms underlying this injury accompanied by apoptosis have yet to be elucidated. The endoplasmic reticulum (ER) stress plays a key part in the regulation of apoptosis. ER stress is defined as accumulation of unfolded or misfolded proteins in the ER. Here, we demonstrated the role of ER stress on Cd-evoked apoptosis in neuronal cells, as well as the neuroprotective effects of the antioxidant alpha-lipoic acid (α-LA) on Cd-induced ER stress and neuronal injury. In vitro, we observed that Cd activated ER associated proteins via the eIF2α-ATF4 pathway in primary rat cerebral cortical neurons. Furthermore, the ER-stress inhibitor salubrinal blocked the dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and significantly reduced the induction of ER stress marker CHOP, the increase of the B-cell lymphoma-2 associate X protein (Bax)/B-cell lymphoma-2 (Bcl-2) ratio, and apoptosis induced by Cd. In addition, Z-ATAD-FMK (a caspase-12 inhibitor) counteracted the Cd-induced activation of caspase-12 and -3, and apoptosis. These in vitro results collectively suggested that ER stress was required for Cd-induced neuronal apoptosis. Importantly, α-LA inhibited the activation of the ER stress eIF2α-ATF4 pathway, the increase of the Bax/Bcl-2 ratio, the activation of caspase-12 and -3, and the apoptosis induced by Cd. In vivo, we also found that the administration of α-LA alleviated Cd-induced neuronal injury, inhibited the activation of the ER stress eIF2α-ATF4 pathway, restored the Bax/Bcl-2 ratio, and prevented the activation of caspase-12 and -3. Taken together, our results demonstrated that Cd triggered protein changes in the ER accompanied by apoptosis via the eIF2α-ATF4 signaling pathway in the neuronal cells of rats, both in vitro and in vivo. Furthermore, we demonstrated for the first time that α-LA protected neurons from Cd-induced injury partly by inhibiting ER stress in rat cerebral cortical neurons.