The natural antioxidant curcumin has been proposed for cancer chemoprevention, as it reduces proliferation of several types of cancer. In this study, we investigated anticancer efficacy of curcumin in two human osteosarcoma cell lines, U2OS and MG-63. The results demonstrated that the proliferation of the osteosarcoma cells was significantly inhibited in a time- and concentration-dependent manner when incubated with curcumin. Furthermore, after being treated with curcumin, the level of apoptosis significantly increased, and the expression level of apoptosis-related proteins increased. The invasion properties of the cell lines decreased gradually. MG-63 cells, which have a P53 gene mutation, were more sensitive to curcumin than U2OS cells. Therefore, curcumin has an obvious inhibition effect on the human osteosarcoma cell lines, and the P53 gene may play an important role in this process. Curcumin is a promising antitumor drug for human osteosarcoma treatment.