Ulcerative colitis (UC) is a diffuse inflammatory disease that occurs in the mucosa of the colon and rectum. Research illustrated that omentin-1 level was significantly lower in the serum of patients with UC. This study systematically examines the emerging roles of omentin-1 in UC and its related mechanisms. Omentin-1 level in dextran sulfate sodium (DSS)-induced mice was examined by Western blot and RT-PCR. The expressions of endoplasmic reticulum (ER) stress-related proteins were detected adopting Western blot with or without the addition of ER stress inducer tunicamycin (TM) in colitis mice. Subsequently, in DSS-induced UC mice, colonic damage was determined by HE staining, body weight, colon length, and disease activity index (DAI). Inflammation and barrier damage were examined by ELISA and Western blot. Cell apoptosis in colon tissues was examined by TUNEL and Western blot. Omentin-1 expressed lowly in DSS-induced colon tissues of UC mice, and its overexpression inhibited ER stress. Additionally, overexpression of omentin-1 also inhibited DSS-induced colon damage, inflammation, barrier damage and cell apoptosis in UC mice; however, these changes were partly abolished by TM administration. In conclusion, omentin-1 attenuates DSS-induced inflammation and barrier damage in UC mice by inhibiting ER stress, suggesting omentin-1 may be a useful target for the treatment of UC.