Curaxin CBL0137 was designed to regulate p53 and nuclear factor-κB simultaneously and exhibits antitumor activity by inhibiting tumor cell proliferation and inducing apoptosis in multiple cancers. However, whether CBL0137 can induce pyroptosis has not yet been reported. This study demonstrated that CBL0137 induces caspase-3/gasdermin E (GSDME)-dependent pyroptosis via the reactive oxygen species (ROS)/BAX pathway. In ovarian cancer cells, CBL0137 inactivated the chromatin remodeling complex which could facilitate chromatin transcription, leading to the decreased transcription of antioxidant genes and oxidation and causing increased ROS levels. BAX was recruited on the mitochondrial membrane by mitochondrial ROS and induced the release of cytochrome c to cleave caspase-3. This led to the cleavage of the N-terminal of GSDME to form pores on the cell membrane and induced pyroptosis. Results of in vivo experiments revealed that CBL0137 also had anti-tumor effects on ovarian cancer cells in vivo. Our study outcomes reveal the mechanisms and targets of CBL0137 inducing pyroptosis in ovarian cancer cells and indicate that CBL0137 is a promising therapeutic agent for ovarian cancer.