Tumor angiogenesis, growth and metastasis are three closely related processes. We therefore explored the effects of (-)-oleocanthal (OC) on the three processes in melanoma and investigated underlying mechanisms. In vitro, OC suppressed proliferation, migration, invasion and induced apoptosis in melanoma cells. In addition, OC inhibited proliferation, migration, invasion and tube formation in human umbilical vascular endothelial cells. In vivo, it exhibited potent activity in suppressing tumor growth in a subcutaneous xenograft model. Furthermore, OC suppressed proliferation and angiogenesis as measured by immunohistochemical staining of Ki-67 and CD31. In addition, OC was found to inhibit metastasis of melanoma in a lung metastasis model. Mechanistically, OC significantly suppressed signal transducer and activator of transcription 3 (STAT3) phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity. OC also downregulated STAT3 target genes, including Mcl-1, Bcl-xL, MMP-2, MMP-9, VEGF, which are involved in apoptosis, invasion and angiogenesis of melanoma. These results support further investigation of OC as a potential anti-melanoma drug.