The purpose of this study is to investigate the effects of Lang-du extract (LDE) from Traditional Chinese Medicine (TCM) Euphorbia fischeriana Steud on the in vitro and in vivo growth of melanoma cells and its molecular mechanisms of action. Our present results have shown that LDE significantly suppressed the in vitro melanoma cell growth in dose- and time-dependent manners. LDE also displayed the synergistic effect with γ-radiation on the reduction of the cell viability in melanoma cells. The animal experimental results further confirmed that compared with the control group without drug treatment, the tumor volume in mice was significantly and time-dependently less in LDE group. The absolute weight of solid tumor in the LDE group was 7-fold lower than that in the control group. Western blot analysis indicated that LDE markedly down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro-apoptotic protein Bax, eventually leading the reduction of Bcl-2/Bax protein ratios both in the cultured melanoma cells and in the tumors from melanoma-bearing mice. In addition, LDE significantly reduced the tumor progression-associated protein levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF), and osteopontin (OPN) in tumors from the LDE-treated mice. Our findings suggest that LDE may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of melanoma and other cancer.