Spinal cord injury (SCI) results in significant degeneration of neurons and axons that leads to permanent impairment in motor, sensory and autonomic function. Thus, development of neuroprotective and neuroregenerative strategies are critical to reduce neuronal damage and facilitate axon regeneration in injured neurons. Our laboratory has uncovered that SCI results in acute and persistent downregulation of Neuregulin-1beta 1 (Nrg-1 β1) after SCI. We demonstrated that restoring the declined levels of Nrg-1β1 fosters oligodendrogenesis and promotes an anti-inflammatory, pro-regenerative response in resident glia and infiltrating leukocytes, which culminates in improved recovery of function after SCI. Nrg-1β1 is well-known for its critical roles in the development, maintenance and physiology of neurons and glia in the developing and adult spinal cord. However, despite this pivotal role, Nrg-1β1 specific effects and mechanisms of action on neuronal injury remain largely unknown in SCI. In this study, we have demonstrated, for the first time, that Nrg-1β1 protects neurons from degeneration in acute and subacute phases of SCI through downregulation of several cell injury pathways implicated in oxidative damage, lipid peroxidation, necrosis and apoptosis. Utilizing a SCI-relevant in vitro model of glutamate excitotoxicity, a major mechanism of neuronal injury in SCI, we have provided direct evidence that Nrg-1 protects neurons by blocking Caspase-3 and mitochondrial mediated cell death mechanisms, and modulation of MAPK and Akt signaling pathways. Altogether, our work provides novel insights into the role and mechanisms of Nrg-1β1 in neuronal injury after SCI and introduces its potential as a new neuroprotective target for this debilitating neurological condition.