BACKGROUND AND PURPOSE Esophageal squamous cell carcinoma (ESCC) is one of the major subtypes of esophageal cancer. More than half of the ESCC patients in the world are in China, and the 5-year survival rate is less than 10%. As a new oral proteasome inhibitor, ixazomib has shown strong therapeutic effect in many solid tumors. In this study, we aimed to investigate the effects of ixazomib on the proliferation inhibition and apoptosis of ESCC cells. EXPERIMENTAL APPROACH We used four human ESCC cell lines, cell viability assay, cell cycle and apoptosis assay, RT-PCR, Western blot, immunohistochemistry and ESCC xenografts model to clarify the roles of the therapeutic effect and mechanism of ixazomib in ESCC. KEY RESULTS Ixazomib significantly inhibited the proliferation and induced apoptosis in ESCC cells. RT-PCR results showed that the expression of endoplasmic reticulum stress-related gene NOXA and c-Myc significant increase after treatment with ixazomib in ESCC cell. Then we knockdown the NOXA and c-Myc by siRNA, the therapeutic effect of ixazomib markedly decrease, which confirmed that c-Myc/NOXA pathway played a key role in the treatment of ESCC with ixazomib. In vivo, the xenograft ESCC model mice were given 10 mg/kg of ixazomib every other day for 30 days. The results showed that the tumor size in the treatment group was significantly smaller than the control group CONCLUSIONS AND IMPLICATIONS These results suggested that ixazomib is known to suppress proliferation and induce apoptosis in an ESCC cell lines, and this effect was likely mediated by increased activation of the c-Myc/NOXA signaling pathways.