Cortical spreading depolarization (SD) is a slow self-propagating wave of mass cellular depolarization in brain tissue, thought to be the underlying cause of migraine scintillating scotoma and aura, and associated with stroke, traumatic brain injury, and termination of status epilepticus. The N-methyl-d-aspartate subtype of glutamate receptor (NMDAR), which gates influx of calcium and is an important trigger of long-term synaptic plasticity, is also a contributor to the initiation and propagation of SD. The current study tested the potential of pharmacological modulation of NMDAR activity through the obligatory co-agonist binding site, to suppress the initiation of SD, and modulate the effects of SD on dendritic spine morphology, in in vitro hippocampal slices. A novel NMDAR functional glycine site partial agonist, GLYX-13, sometimes completely prevented the induction of SD and consistently slowed its rate of propagation. The passage of SD through the hippocampal CA1 region produced a rapid retraction of dendritic spines which reversed after neuronal depolarization had recovered. GLYX-13 improved the rate and extent of return of dendritic spines to their original sizes and locations following SD, suggesting that NMDAR modulators can protect synaptic connections in the brain from structural alterations elicited by SD. These data indicate that NMDAR modulation to renormalize activity may be an effective new treatment strategy for suppression or amelioration of the contribution of SD to short and long-term symptoms of migraine attacks, as well as the effects of SD on tissue damaged by stroke or traumatic brain injury.