Curcumin, a polyphenol compound, possesses potent pharmacological properties in preventing cancers, which make it as a potential anti-cancer mediator. However, it is still unknown that whether Curcumin induced melanoma A375 cell was associated with oxidative stress. Here, we firstly found a fascinating result that Curcumin could reduce the proliferation and induced apoptosis of human melanoma A375 cells. Meanwhile, IC₅₀ of Curcumin on A375 cells is 80μM at 48h. In addition, Curcumin caused oxidative stress through inducing further ROS burst, decreasing GSH, and wrecking mitochondria membrane potential (MMP), which were reversed by ROS inhibitor N-acetylcysteine (NAC). Moreover, MMP disruption led to the release of Cytochrome c from mitochondria and subsequently led to intracellular apoptosis. Furthermore, we found that ROS-dependent HIF-1α and its downstream proteins also play an important role on Curcumin induced apoptosis. In conclusion, our results shed new lights on the therapy of melanoma that Curcumin may be a promising candidate.