Spinal cord injury (SCI) results in degeneration of oligodendrocytes that leads to demyelination and axonal dysfunction. Replacement of oligodendrocytes is impaired after SCI, owing to the improper endogenous differentiation and maturation of myelinating oligodendrocytes. Here, we report that SCI-induced dysregulation of neuregulin-1 (Nrg-1)–ErbB signaling may underlie the poor replacement of oligodendrocytes. Nrg-1 and its receptors, ErbB-2, ErbB-3, and ErbB-4, play essential roles in several aspects of oligodendrocyte development and physiology. In rats with SCI, we demonstrate that the Nrg-1 level is dramatically reduced at 1 day after injury, with no restoration at later time-points. Our characterisation shows that Nrg-1 is mainly expressed by neurons, axons and oligodendrocytes in the adult spinal cord, and the robust and lasting decrease in its level following SCI reflects the permanent loss of these cells. Neural precursor cells (NPCs) residing in the spinal cord ependyma express ErbB receptors, suggesting that they are responsive to Nrg-1 availability. In vitro, exogenous Nrg-1 enhanced the proliferation and differentiation of spinal NPCs into oligodendrocytes while reducing astrocyte differentiation. In rats with SCI, recombinant human Nrg-1β1 treatment resulted in a signifcant increase in the number of new oligodendrocytes and the preservation of existing ones after injury. Nrg-1β1 administration also enhanced axonal preservation and attenuated astrogliosis, tumor necrosis factor-α release and tissue degeneration after SCI. The positive effects of Nrg-1β1 treatment were reversed by inhibiting its receptors. Collectively, our data provide strong evidence to suggest an impact of Nrg-1–ErbB signaling on endogenous oligodendrocyte replacement and maintenance in the adult injured spinal cord, and its potential as a therapeutic target for SCI.