We previously reported a novel target of the drug memantine, ATP-sensitive K⁺ (K_ATP) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer’s disease (AD) model mice. Memantine also inhibited Kir6.1 and Kir6.2 K_ATP channels and elevated intracellular Ca²⁺ concentrations in neuro2A (N2A) cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. We confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. In the present study, we focus the complex resinous substance, propolis that is relevant as a therapeutic target for AD. We confirmed that propolis further enhances the rescue of cognitive deficits by the memantine in AD model mice. In in vitro studies, propolis significantly increased intracellular Ca²⁺ concentration and calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation in Kir6.2-overexpressed N2A cells treated with memantine. Our study demonstrates that propolis increases ATP contents and promotes the amelioration of cognitive deficits rescued by memantine via Kir6.2 channel inhibition in the CA1 region.