The molecular mechanisms of the contribution of angiotensin II type-1 receptor blockers to neuronal protection are still unclear. Here, we investigated the effect of angiotensin II type-2 (AT2) receptor stimulation on neurons and cognitive function involving a new neuroprotective factor, methyl methanesulfonate sensitive 2 (MMS2). Angiotensin II treatment of neurospheres enhanced their differentiation and increased MMS2 expression. Knockdown of the MMS2 gene by small interference RNA (siRNA) significantly reduced the number of neurospheres, with loss of sphere formation. An angiotensin II type-1 receptor blocker, valsartan, enhanced such neurosphere differentiation and MMS2 induction, whereas an AT2 receptor antagonist, PD123319, inhibited them. After mice underwent permanent middle cerebral artery occlusion, AT2 receptor mRNA expression was significantly increased in the ischemic side of the brain. Passive avoidance rate to evaluate cognitive function was significantly impaired in AT2 receptor null (Agtr2-) mice compared with wild-type mice. Treatment with valsartan prevented the cognitive decline in wild-type mice, but this effect was weaker in Agtr2- mice. In ischemic brain regions, MMS2 was increased in wild-type mice, but not in Agtr2- mice. Valsartan also enhanced MMS2 expression to a greater degree in wild-type mice. Finally, intracerebroventricular administration of MMS2 siRNA showed more impaired avoidance rate after middle cerebral artery occlusion compared with that in control siRNA-transfected mice. These findings experimentally support the clinical evidence and indicate a unique mechanism of the AT2 receptor in brain protection.