Objective To investigate the protective effect of VEGF receptor 2 (VEGFR2) on retinal cone photoreceptors under hypoxia condition. Methods Eight-week-old cone-specific VEGFR2-knockout (KO) mice and wild-type (WT) C57BL/6 mice received intravenous injection of 8 mmol/L cobalt chloride in the right eyes for hypoxia condition and PBS in the left eyes for control, with 6 mice in each group. On the next day electroretinogram (ERG) was conducted to evaluate the photoreceptor function, and immunofluorescence colocalization was used to determine the density and morphology of cone photoreceptors. Results In KO and WT groups, hypoxia eyes had significantly decreased a-wave and b-wave amplitudes in scotopic ERG compared with PBS control eyes (P<0.01), but with no significant difference between hypoxia eyes of KO and WT groups (P>0.05). In both KO and WT groups, the hypoxia eyes also had significantly decreased a-wave and b-wave amplitude in photopic ERG compared with PBS control eyes (P<0.01), and the decrease in KO mice was more significant than that in WT group (P<0.05, P<0.01), indicating the decrease of cone function in KO animal. Morphology examination showed noticeable changes under hypoxia condition in both KO and WT groups, showing decreased density, shortened appearance, and disordered arrangement, with the changes in KO group being more noticeable. Conclusion VEGFR2 has a protective effect on cone photoreceptors under hypoxia condition.