Mechanistic studies have demonstrated that apoptosis is key to the pathogenesis of spinal cord ischemia/reperfusion injury (SCIRI), and that endoplasmic reticulum (ER) stress-associated apoptosis contributes to SCIRI. Importantly, strong evidence has shown that xenon (Xe) has neuroprotective effects. This study investigated whether Xe postconditioning had beneficial effects on SCIRI by inhibiting ER stress-associated neuronal apoptosis. A spinal cord I/R rat model was induced by abdominal artery occlusion for 85 min and reperfusion. Subsequently, Xe postconditioning (50% Xe) was administered 1 h after 1 h of reperfusion. We showed that after SCIRI, rats displayed obvious serious spinal cord damage after reperfusion for 4 h, morphological changes, and neuronal damage associated with ER stress-induced apoptosis. However, spinal cord damage above was attenuated in response to Xe treatment. Furthermore, administration of the ER stress inhibitor sodium 4-phenylbutyrate strongly decreased ER stress-induced apoptosis following SCIRI. This study highlights that Xe postconditioning inhibits ER stress activation, which contributes to alleviate SCIRI by suppressing neuronal apoptosis.