Advanced metastatic melanoma, one of the most aggressive skin malignancies, is currently without reliable therapy. The process of angiogenesis is crucial for progression and metastasis of the majority of solid tumors including melanomas. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone which exerts many pharmacological activities against cancer-inflammation. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we demonstrate that mangiferin interferes with inflammation, lipid and calcium signaling which selectively inhibits multiple NFkB target genes including interleukin-6, tumor necrosis factor, interferon gamma, vascular endothelial growth factor receptor 2, plasminogen activator urokinase, matrix metalloprotease 19, C-C Motif Chemokine Ligand 2 and placental growth factor. This abrogates angiogenic and invasive processes and capillary tube formation of metastatic melanoma cells as well as human placental blood vessel explants in-vitro and blocks angiogenesis characteristic of the chicken egg chorioallantoic membrane assay and in melanoma syngeneic studies in vivo . The results obtained in this research illustrate promising anti-angiogenic effects of the natural glucosylxanthone mangiferin for further (pre)clinical studies in melanoma cancer patients.