Background: Cortical spreading depolarization (CSD) is associated with poor outcomes following traumatic brain injury (TBI). Here we aimed to: (1) determine the effect of NMDA-receptor antagonism on CSDs in healthy and TBI animals in vivo; and (2) conduct a randomized pre-clinical trial (RCT) of memantine for prevention neurological decline following repetitive mild TBI (rmTBI). Methods: Rodents received either one moderate (n = 23) or four daily mild (rmTBI; n = 30) head impacts (weight drop). Sham animals received brief anesthetic without TBI (n = 40). 93 animals underwent cranial window surgery with electrocorticographic (ECoG) monitoring and electrically triggered CSDs. Ketamine (100uM topical or 25 mg/kg IP) and memantine (10 mg/kg IP) were tested in vivo. An RCT was conducted (N=31) using memantine (10 mg/kg) or saline (2.5 cc/kg) for rmTBI with daily neurobehavioural testing. Results: In TBI animals, ketamine or memantine inhibited CSDs in 44-88%, and 50-67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44-75% and 52-67%, and duration by 39-87% and 61-78%, respectively. RCT animals that received memantine had higher mean neurological scores (9.27 (SD 3.08) vs. 5.56 (SD 3.05), p< 0.001) vs. saline. Conclusions: Memantine suppressed CSDs following TBI, in vivo. In a pre-clinical RCT of rmTBI, memantine prevented neurological decline.