SCIRR39 is an identified upregulated gene in rat primary neuron injury and/or regeneration process. However, roles of SCIRR39 in the regeneration of central nervous system (CNS) injury are still largely unexplored. Using real-time quantitative PCR and Western blotting, SCIRR39 expression was detected in oligodendrocyte precursor cells (OPCs) and oligodendrocytes. Moreover, the results from cell proliferation and cell cycle indicated that SCIRR39 inhibited OPCs proliferation and induced cell cycle arrest in G0/G1 and G2/M phases. Importantly, SCIRR39 positively regulated OPC differentiation and the expression of myelin basic protein. We also examined the effect of SCIRR39 on expression of myelin-associated inhibitory factors, including myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo A. Nogo A level was markedly regulated by SCIRR39 overexpression or knockdown in oligodendrocytes and cortical neurons co-cultures, while the expression of MAG and OMgp was not obviously changed by SCIRR39 overexpression or knockdown. Taken together, our results indicate the important role of SCIRR39 either in OPC differentiation or in axon myelination, and may provide a new therapeutic target for the treatment of CNS injury.