Bortezomib, a first‑in‑class proteasome inhibitor, is a standard method of treatment in multiple myeloma. In the present study, the therapeutic effect of bortezomib was evaluated in an ulcerative colitis model induced by dextran sulfate sodium (DSS) in mice, and the mechanism of action was also investigated. Mice were administered with 3% DSS drinking water for 7 consecutive days and then they were intraperitoneally treated with bortezomib (0.2, 0.6 or 1 mg/kg) for 1, 3 or 7 days. Mice in the control group and the DSS group were provided the same volume of PBS, respectively. Body weight, stool characteristics and hematochezia were observed. Serum levels of tumor necrosis factor‑α (TNF‑α), C‑reactive protein (CRP), albumin (ALB) and colonic activity of superoxide dismutase (SOD) were evaluated using specific kits. The expression of the transcription factor nuclear factor‑κB (NF‑κB) p65 gene and the DNA‑binding activity of NF‑κB protein were also evaluated. Administration of bortezomib attenuates colonic inflammation in mice. After 3 or 7 days of treatment, Disease Activity Index (DAI) as well as histological scores and NF‑κB p65 protein expression were significantly reduced in mice treated with bortezomib at a dose of 0.6 or 1 mg/kg/day. Furthermore, it was also revealed that bortezomib was able to reduce serum levels of CRP and TNF‑α caused by DSS and increase the level of ALB in serum and the activity of SOD in colonic tissues. These results demonstrated that bortezomib exerts a protective effect on DSS‑induced colitis, and its underlying mechanisms are associated with the NF‑κB gene inhibition that mitigates colon inflammatory responses in intestinal epithelial cells.