Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the central nervous system. Mounting evidence suggests that receptor tyrosine kinases (RTKs) are crucial for oligodendrocyte differentiation and myelination in the CNS. It was recently reported that discoidin domain receptor 1 (Ddr1), a collagen-activated RTK, is expressed in oligodendrocyte lineage. However, its specific expression stage and functional role in oligodendrocyte development in the CNS remain to be determined. In this study, we report thatDdr1is selectively upregulated in newly differentiated oligodendrocytes in the early postnatal CNS and regulates oligodendrocyte differentiation and myelination.Ddr1knock-out mice of both sexes displayed compromised axonal myelination and apparent motor dysfunction.Ddr1deficiency alerted the ERK pathway, but not the AKT pathway in the CNS. In addition,Ddr1function is important for myelin repair after lysolecithin-induced demyelination. Taken together, the current study described, for the first time, the role ofDdr1in myelin development and repair in the CNS, providing a novel molecule target for the treatment of demyelinating diseases.