SET-domain-containing 2 (SETD2) is known as the major trimethyltransferase that regulates the methylation of histone H3 lysine 36 (H3K36), which has been found frequently mutated in IBD samples. Although SETD2 deficiency has been proven to modulate oxidative stress, the specific mechanisms of SETD2 in IBD are still little known. To investigate the possible role of SETD2 in IBD, we generated and genotyped epithelium-specific deletion of Setd2 (Setd2Vil-KO) progeny mice to establish mice IBD pathology model and then studied molecular expression differences at mRNA and protein levels in the intestinal epithelial tissue of Setd2Vil-KO mice. Compared with Setd2F/F mice, the tissue of Setd2Vil-KO mice showed increases in oxidative stress and cell apoptosis level via RT-qPCR, while TUNEL assay and immunofluorescence showed significantly enhanced apoptotic signaling and FasL expression. Together, our findings highlight that SETD2 regulates oxidative stress and FasL-induced apoptosis in Setd2Vil-KO mice intestinal epithelial cells through epigenetics mechanisms, which plays an essential role in IBD pathogenesis. Therefore, our study provides new insights into the prevention and therapy of IBD from the perspective of epigenetic regulation.