To investigate the effect and mechanisms of melitensin on angiogenesis in endothelial cells after brain ischemia-reperfusion injury through network pharmacology，molecular docking，and cell experiments.Methods:Human brain microvascular endothelial cells(HBMECs) were treated with oxygen-glucose deprivation/reoxygenation(OGD/R).The cells were randomly divided into normal，model，butylphthalide treatment，and OGD/R+melitensin(12.5，25，50 μmol/L) groups.Cell viability was measured using the MTT assay，cell migration was evaluated by scratch assay，tube formation ability was assessed using the tube formation assay，and the levels of lactate dehydrogenase(LDH)，tumor necrosis factor-α(TNF-α)，and vascular endothelial growth factor(VEGF) were detected by enzyme-linked immunosorbent assay(ELISA).Target genes of melitensin for treating ischemic stroke(IS) were identified using databases and online platforms，and the protein-protein interaction(PPI) network was constructed via String and Cytoscape software.Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted，and molecular docking was performed on key targets in core pathways.Finally，in vitro validation was performed using quantitative real-time PCR(RT-qPCR) and Western blot.Results:Melitensin significantly improved cell viability，promoted cell migration，and enhanced tube formation ability.It also reduced LDH and TNF-α levels while increasing VEGF levels(P<0.05，P<0.01).Network pharmacology analysis identified 62 common drug-disease targets and 9 core therapeutic targets.Enriched key pathways included VEGF，IL-17，MAPK，and TNF signaling pathways.Molecular docking showed that Melitensin had a good binding affinity with VEGF and VEGF receptor 2(VEGFR2).In vitro experiments confirmed that melitensin upregulated the mRNA and protein expression levels of angiopoietin-1(Ang-1)，VEGF，and VEGFR2(P<0.05，P<0.01).Conclusion:Melitensin may exert therapeutic effects on IS by regulating the VEGF signaling pathway and promoting angiogenesis.