Enhanced glutamate release and inflammation play an important role in the pathogenesis of developmental brain injury. Although N-methyl-d-aspartate receptor (NMDAR) antagonists potently attenuate neonatal brain damage in several animal models, they can also impact trophic functions in the developing brain. As a consequence, high-affinity NMDAR antagonists have been shown to trigger widespread apoptotic neurodegeneration in the newborn brain. Dextromethorphan (DM), a low-affinity NMDAR antagonist with anti-inflammatory properties, may be neuroprotective against excitotoxic and inflammation-enhanced excitotoxic brain injury, without the associated stimulation of apoptotic degeneration. Using an established newborn mouse model of excitotoxic brain damage, we determined whether systemic injection of DM significantly attenuates excitotoxic lesion size. We investigated several doses and time regimens; a dose of 5 µg/g DM given in a combination of both pre-injury and repetitive post-injury treatment proved most effective. DM treatment significantly reduced lesion size in gray and white matter by reducing cell death as shown by a decreased Fluoro-Jade B staining and caspase-3 activation. Pre-treatment with interleukin-1β and lipopolysaccharide enhanced NMDAR-mediated excitotoxic brain injury and microglial cell activation. This sensitizing effect was abolished by DM treatment, as the effectiveness of DM in reducing lesion size and microglial cell activation was similar to phosphate-buffered saline-pre-treated controls. In all cases, no gender-specific differences were detected. DM treatment did not trigger any apoptotic neurodegeneration (caspase-3 cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Fluoro-Jade B staining). Although functional parameters were not measured, our data corroborate reports that DM is neuroprotective and that it may therefore improve functional outcome following perinatal brain injury.