Despite promising benefits, anti-angiogenic strategies have revealed several drawbacks, which necessitate development of novel approaches in cancer therapy strategies including non-small-cell lung cancer, as one of the leading causes of cancer death, all over the world. Combination of flavonoids could be a safe and effective option to synergize their impact on mechanisms controlling tumor angiogenesis. In this study, we have investigated the plausible synergism of epigallocatechin-3-gallate (EGCG) and silibinin on endothelial cells, for the first time. Cell viability and migration were evaluated by survival and wound healing assays, respectively. Then, we assessed the expression of VEGF, VEGFR2, and miR-17-92 cluster using real-time polymerase chain reaction in endothelial-tumor cell and endothelial-fibroblast coculture models. EGCG ± silibinin suppressed endothelial and lung tumor cell migration in lower than 50% toxic doses. VEGF, VEGFR2, and pro-angiogenic members of the miR-17-92 cluster were downregulated upon treatments. Specifically, the combination treatment upregulated an anti-angiogenic member of the cluster, miR-19b. Our data provides evidence to utilize the EGCG and silibinin combination as a novel approach to target tumor angiogenesis in the future.