Tumor growth and metastasis depend on angiogenesis triggered by chemical signals, such as vascular endothelial growth factor (VEGF), released from tumor cells. Therefore, the specific perturbation of angiogenesis has been considered a powerful strategy for the treatment of cancer. Herein, we report that tricin, 4',5,7-trihydroxy-3',5'-dimethoxyflavone, exhibits potent antiangiogenic activity in vitro. Tricin effectively suppressed the proliferation as well as VEGF-induced invasion and tube formation of human umbilical vein endothelial cells (HUVECs) at subtoxic doses. Furthermore, tricin significantly inhibited the angiogenesis of the chorioallantoic membrane from growing chick embryos without showing cytotoxicity. We also found that tricin blocked tumor cell-induced angiogenesis. Notably, tricin downregulated not only the VEGFR2 signal transduction by reducing reactive oxygen species (ROS) generation in endothelial cells, but also the expression of VEGF by inhibiting hypoxia inducible factor-1α (HIF-1α) accumulation in tumor cells. Moreover, combined treatment with tricin and bevacizumab, an anti-VEGF drug, ameliorated the antiangiogenic effect of bevacizumab. Taken together, our findings demonstrate for the first time that tricin possesses promising antiangiogenic potential and thus may be applied to anticancer therapy by targeting tumor angiogenesis.