This study was to investigate the cell killing effect of chlorin-e6 (Ce6) mediated sonodynamic therapy (SDT) on human leukemia U937 cells and explore the role of ERK signal pathway in the process. The ultrastructure changes of U937 cells induced by ultrasonic irradiation were evaluated by scanning electron microscope (SEM) and transmission electron microscope (TEM). The viability of cells was evaluated by viacount assay. Apoptosis was analyzed using flow cytometer as well as fluorescence microscopy with 4'-6-diamidino-2-phenylindole (DAPI) staining. Western blotting was used to analyze the expression of mitogen-activated protein kinase (MAPK). Intracellular reactive oxygen species (ROS) and mitochondria membrane potential (MMP) levels were also analyzed by flow cytometer after exposure. Our experiments showed that several distinct sonochemical effects were found after Ce6-mediated SDT treatment. Western blotting analysis indicated that the MAPK were activated. Especially, pre-treatment with ERK inhibitor U0126 could additionally enhance SDT-induced cell viability loss, early- and late-apoptotic rate, chromatin condensation, DNA fragmentation and caspase-3 activation. Besides, a mass of ROS accumulation and a conspicuous loss of mitochondrial membrane potential were detected in U937 cells. These findings suggested ERK signal pathway may deliver a survival signal which counteracts SDT-induced cell death, while combination with U0126 could significantly potentiate the SDT-induced cytotoxic effect in U937 cells.