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Repetitive mild traumatic brain injury (rmTBI; eg, sports concussions) is a common injury that has been shown to result in significant cognitive impairment and yet, current targeted therapies for rmTBI are lacking. There is a paucity of preclinical and clinical data regarding NMDAR antagonist efficacy in the rmTBI setting. Evidence from other injury models indicates that strategies mitigating N-methyl-daspartate (NMDA) receptor (NMDAR)-mediated excitotoxicity might mitigate rmTBI-induced neurologic deficits. This is particularly attractive as NMDAR antagonists are widely-available and already in clinical use. Thus, we investigated whether a posttraumatic NMDAR blockade protects against adverse functional and histopathological sequelae in an established mouse rmTBI model. Immediately after the last rmTBI injury (5 injuries in 5 days), mice were randomized to receive memantine treatment or vehicle. Functional outcomes were assessed by motor, anxiety/impulsivity and mnemonic behavioral tests. At the synaptic level, NMDAR-dependent long-term potentiation (LTP) was assessed in isolated neocortical slices. At the molecular level, the magnitude of microgliosis and tau hyper-phosphorylation was tested by immunostaining, while NMDAR subunit expression was evaluated by western blot and polymerase chain reaction (PCR). Compared to injured vehicle treated mice, injured memantine treated mice had partially mitigated APP upregulation and reductions in tau phosphorylation. Memantine also ameliorated deficits in LTP and a decline in NMDARs. Furthermore, treatment with memantine in injured mice reduced moicrogliosis after rmTBI. Finally, Open Field testing showed that injured, memantine-treated mice spent less time in the wall zone compared to injured vehicle treated mice. Elevated Plus Maze also revealed that injured, memantine-treated mice performed more like sham mice compared to injured, vehicle-treated mice. No improvement in learning and memory was observed in the injured, memantine-treated group. Our results indicate that early treatment of memantine ameliorates TBI-mediated histopathological changes at the molecular and electrophysiological levels. Furthermore, memantine improves certain behavioral outcomes after rmTBI. This data raises the prospects for therapeutic, post-concussive NMDAR antagonism. Further evaluation of the therapeutic window and dosing for treatment is warranted. [ABSTRACT FROM AUTHOR]