Orexin-A is a newly identified neuropeptide expressed in the lateral areas of the hypothalamus that plays a role in various physiological functions, including regulation of glucose metabolism. We have previously reported that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of orexin-A on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Neuronal damage was estimated by histological and behavioral analysis after MCAO. Intracerebroventricular administration of orexin-A (2.5, 25, or 250 pmol/mouse) significantly and dose-dependently suppressed the development of post-ischemic glucose intolerance on day 1 after MCAO and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptor were decreased, whereas those of gluconeogenic enzymes were increased on day 1 after MCAO. Furthermore, these expressions were completely recovered to normal levels by orexin-A and were reversed by the administration of SB334867, a specific orexin-1 receptor antagonist. These results suggest that regulation of post-ischemic glucose intolerance by orexin-A suppressed cerebral ischemic neuronal damage.