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Abstract Myelination is a process tightly regulated by a variety of neurotrophic factors. Here, we show—by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21(PDGFB-rhEPO) and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s (Sox10-cre;EpoRfx/fx mice)—a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Conversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Furthermore, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week and EPO increases the postnatal expression of essential oligodendrocyte pro-differentiation and pro-maturation (Nkx6.2 and Myrf) transcripts, and the Nfatc2/calcineurin pathway. In contrast, ablation of EPORs from OPCs inactivated the Erk1/2 pathway and reduced the postnatal expression of the transcripts. Our results reveal developmental time windows in which EPO therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.