We investigated the molecular mechanism of curcumol-induced apoptosis in bladder cancer cells. The mitochondrial membrane potential was measured using JC-1 staining. ROS generation of bladder cancer cells was determined using the DCFH staining method. The apoptosis of bladder cancer cells was examined using the Annexin V-FITC and PI double-staining method. Enforced expression of EZH2 in bladder cancer cells was accomplished by transfecting an EZH2 expression plasmidinto EJ and T24 cells. siRNAs targeting EZH2 were used to inhibit endogenous expression of EZH2. Curcumol dose-dependently inhibited proliferation and colony formation and induced apoptosis in EJ and T24 bladder cancer cells. These effects correlated with decreased accumulation of EZH2. In addition, suppression of EZH2 enhanced the inhibitory effects of curcumol on cell growth and colony formation and increased curcumol-induced apoptosis. Conversely, enforced expression of EZH2 ameliorated the inhibitory effects of curcumol on cell growth and colony formation and decreased curcumol-induced apoptosis in EJ and T24 cells. We also found that suppression of EZH2 induced ROS generation and MMP loss in both EJ and T24 cells. Conversely, up-regulation of EZH2 suppressed ROS generation and MMP loss. Our data indicate that curcumol inhibits proliferation and induces apoptosis by targeting EZH2 and modulating the mitochondrial apoptosis pathway.