Background Melanoma is a life-threatening cancer characterized with a potentially metastatic tumor of melanocytic origin. Improved methods or novel therapies are urgently needed to eliminate the development of metastases. Artesunate is a semi-synthetic derivative of artemisinin used for trarment of malaria and cancer. The purpose of this study was to investigate the anti-cancer effect of artesunate and the role on STAT3 signaling in A375 human melanoma cell line. Methods Melanoma cells were treated with artesunate at concentrations of 0-5 mu M for 24 and 48 h. The inhibition of cell viability, colony formation, migration, invasion, adhesion, percentage of apoptotic cells, and expressions of signal transducer and activator of transcription-3 (STAT3) and related proteins were examined. Results Artesunate inhibited cellular proliferation of cancer cells by induction of apoptosis at sub-toxic doses. Cells treated with artesunate showed an inhibition in adhesion to extracellular matrix substrate matrigel and type IV collagen. Artesunate treatment showed a decreased cellular migration, invasion, and colony formation in melanoma cells. Artesunate also inhibited STAT3 and Src activations and STAT3 related protein expressions; such as metalloproteinase 2 (MMP-2), MMP-9, Mcl-1, Bxl-xL, vascular endothelial growth factor (VEGF), and Twist. Moreover, overexpression of constitutively active STAT3 in A375 cells attenuated the anti-proliferative, apoptotic and anti-invasive effects of artesunate. Conclusion The results obtained from this study demonstrated that the anticancer activity of artesunate occurred via STAT3 pathway and its target proteins. Therefore, it can be suggested that artesunate may be an important candidate molecule in the treatment of melanoma.