Adrenomedullin (AM) is a vasodilating peptide secreted mainly from vascular wall, and its expression is markedly enhanced after stroke. We developed novel AM-transgenic (AM-Tg) mice and performed middle cerebral artery occlusion for 20 min (20m-MCAO) to examine the effects of AM on degenerative and regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34+ cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with anti-inflammatory and neuro-protective effects resulted in improved recovery of motor function. In vitro, AM exerted direct anti-apoptotic and neurogenic actions on neuronal cells. In summary, this study provides a basis for new strategy to rescue ischemic brain by AM through its multiple hormonal actions which concurrently lead to anti-inflammation, neuro-protection and vasculo-neuro-regeneration.