The aim of this study was to determine whether F-box and WD repeat domain-containing 7 (FBXW7) can mediate the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway to affect neonatal hypoxic-ischemic brain damage (HIBD) in neonatal rats. HIBD rats were treated with LV-shFBXW7. Cerebral infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, while microvessel density (MVD) was evaluated by immunohistochemistry. Learning and memory were tested using the Morris water maze (MWM) test. FBXW7 and HIF-1α/VEGF signaling pathway proteins were measured by Western blotting. Brain microvascular endothelial cells (BMECs) were isolated to establish an oxygen-glucose deprivation (OGD) model to evaluate treatment with FBXW7 siRNA. Cell viability was detected using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, while cell migration was evaluated using a wound healing assay. The tube formation of BMECs was also assessed. The results demonstrated that HIBD rats exhibited increased protein expression of FBXW7, HIF-1α, and VEGF. HIBD rats also displayed increased cerebral infarct size, prolonged escape latency and a decreased number of platform crossings. However, HIBD rats treated with LV-shFBXW7 exhibited reversal of these changes. experiments showed that BMECs in the OGD group had significantly decreased cell viability, shorter vascular lumen length, and shorter migration distance than cells in the control group. Moreover, silencing FBXW7 promoted proliferation, tube formation and migration of BMECs. Taken together, silencing FBXW7 upregulates the HIF-1α/VEGF signaling pathway to promote the angiogenesis of neonatal HIBD rats after brain injury, reducing infarct volume and improving recovery of nerve function in HIBD rats.