Here we report that a novel target of mementine, ATP-sensitive K⁺ (K_ATP) channels are implicated in improvement of cognitive and mental disorders. K_ATP channels Kir6.1 or Kir6.2 are composed with sulfonylurea receptors (SURs), which are distributed both in peripheral tissues and central nervous system. We confirmed that memantine improves both memory impairment and perturbed NMDAR-dependent LTP in APP23 mouse hippocampus. In addition, we also confirmed that Kir6.2 heterozygous mutant mice exhibit severe memory deficits and hippocampal LTP impairment that could not be rescued by memantine administration. By contrast, we show that memantine enhances adult neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors via inhibition of the K_ATP channel in olfactory bulbectomized (OBX) mice. In addition, both the improvement of depressive-like behaviors and increase in BrdU-positive neurons in the DG following treatment with memantine were unapparent in OBX-treated Kir6.1 heterozygous (+/-) mice but not OBX-treated Kir6.2 heterozygous (+/-) mice. Taken together, we propose a novel strategy that memantine inhibits K_ATP channel activities, thereby improving cognitive/mental disorders in AD patients.