I recently found that cerebral ischemic stress per se causes hyperglycemia (i.e., post-ischemic glucose intolerance) and suppression of post-ischemic glucose intolerance might be important to improve prognosis. Here, I analyzed the efficacy of suppression of post-ischemic glucose intolerance using orexin-A (OXA) endogenous neuropeptide as a novel therapeutic strategy against cerebral ischemic neuronal damage. OXA in hypothalamus plays a role in many physiological functions including regulation of glucose metabolism. I previously found that the development of post-ischemic glucose intolerance is suppressed by OXA. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic OXA-mediated suppression of post-ischemic glucose intolerance and neuronal damage. Intrahypothalamic administration of OXA significantly suppressed the development of post-ischemic glucose intolerance on day 1 and of neuronal damage on day 3 after middle cerebral artery occlusion (MCAO). In the liver, MCAO-induced decrease in insulin receptors and increase in gluconeogenic enzymes on day 1 was recovered to control levels by OXA; these effects were reversed by hepatic vagotomy. In the medulla oblongata, OXA induced co-localization of the cholinergic neuronal marker choline acetyltransferase with orexin-1 receptor and c-Fos. These results suggest that the vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates neuroprotection by hypothalamic OXA.