Glutamatergic cytotoxicity mediated by overactivation of N-methyl-d-aspartate receptors (NMDARs) is implicated in numerous neurological disorders. To be therapeutically viable, NMDAR antagonists must preserve physiological role of synaptic NMDARs (sNMDARs) in synaptic transmission and block only excessive pathological activation of NMDARs. Here we present a novel NMDAR antagonist that satisfies this two-fold requirement by exploiting spatial differences in NMDAR subcellular locations. Specifically, we designed a hybrid nanodrug (AuM) to be larger than the synaptic cleft by attaching memantine, NMDAR antagonist, via polymer linkers to a gold nanoparticle. We show that AuM efficiently and selectively inhibited extrasynaptic NMDARs (eNMDARs), while having no effect on sNMDARs and synaptic transmission. AuM exhibited neuroprotective properties both in vitro and ex vivo during such neurotoxic insults as NMDAR-mediated cytotoxicity in cerebrocortical cell culture and oxygen-glucose deprivation in acute hippocampal slices. Furthermore, AuM prevented dendritic spine loss triggered by Aβ oligomers in organotypic hippocampal slices and was more effective than free memantine. Using a novel rational design strategy, we demonstrate a proof of concept for a new class of neuroprotective drugs that might be beneficial for treatment of several neurological disorders.