Retinopathy of prematurity (ROP), a leading cause of blindness in premature infants, is characterized by retinal vaso-obliteration during hyperoxia and pathological neovascularization (NV) in relative hypoxia phase. Current treatments, which focus on the late stages of pathological neovascularization, are associated with numerous side effects. Studies demonstrated that discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase, inhibits the experimental choroidal neovascularization and participates in tumor angiogenesis. However, the role of DDR2 in ROP and underlying mechanisms is unclear. In this study, we initially found that DDR2 expressed during mouse physiological retinal vascular development and significantly decreased in vaso-obliteration phase followed by increase during pathological neovascularization phase in mouse oxygen-induced retinopathy (OIR) model. Early upregulation of DDR2 before hyperoxia attenuates oxygen-induced vaso-obliteration, reduces pathological neovascularization, and promotes retinal vascular maturation. Additionally, DDR2 upregulation increased the number of microglia around retinal blood vessels and induced anti-inflammatory M2 polarization. Furthermore, the STAT6/TGF-β signaling pathway suppressed during hyperoxia was activated after DDR2 upregulation. In conclusion, DDR2 attenuated vaso-obliteration and inhibited pathological neovascularization by switching the microglia polarization from M1 to M2 phenotype via the STAT6/TGF-β signaling pathway in OIR. This suggests that DDR2 could be a novel target for the early treatment of ROP.