Aims: To investigate the effect of erythropoietin (EPO) on the differentiation of neural stem cells (NSCs)/neural progenitors (NPs) in the treatment of hypoxic-ischemic injury and its potential mechanisms. Methods: Fetal NSCs/NPs were treated with EPO after oxygen and glucose deprivation/reoxygenation (OGD/R). Cell viability, proliferation, and differentiation of NSCs/NPs were detected by CellTiter-Glo, Edu assay, flow cytometry, and quantitative realtime PCR (qPCR). Immunofluorescence staining, co-immunoprecipitation (Co-IP), and western blotting were used to test the existence of EPO receptor/beta common receptor (EPOR/beta CR) heterodimer on NSCs/NPs and the possible pathway. Results: EPO treatment at different time points increased cell viability without affecting proliferation. EPO treatment immediately after OGD/R promoted oligodendrocyte and astrocyte differentiation, while decreasing neuronal differentiation of NSCs/NPs. EPOR/beta CR heterodimer existed on the cell surface of the fetal cortical NSCs/NPs, EPO treatment significantly increased the mRNA expression of pCR and elevated the correlation between EPOR and OCR levels. In addition, mass spectrometry analysis identified Syne-1 as a downstream signaling molecule of the EPOR/beta CR heterodimer. Immunofluorescence staining and western blotting indicated that the beta CR/Syne-1/H3K9me3 pathway was possibly involved in the differentiation of fetal neural stem cells into the glial cell effect of EPO. Conclusion: EPO treatment immediately after OGD/R could not facilitate fetal NSCs/NPs neurogenesis but promoted the formation of the EPOR/beta CR heterodimer on fetal NSCs/NPs, which mediates its function in glial differentiation.