Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by sudden attacks of remissions and exacerbations with increased incidence of cancer colon. The present study aims to determine the possible ameliorative mechanisms of Olmesartan in UC induced experimentally in rat. Methods: Adult albino rats were randomly grouped into control, UC model non treated group: Rats received dextran sodium (DSS) orally for 21 days with intra-colic administration of acetic acid (AA) for 3 consecutive days for induction of UC model, Olmesartan (1, 5, 10mg/kg/orally) and UC + Olmesartan in different doses (1 mg, 5 mg and 10 mg/kg/day orally). Results: DSS orally and AA intra-rectal produced sever colitis manifested by significant weight loss, watery and bloody diarrhea. Significant increase in serum and colonic tissue levels of tumor necrosis factor alpha and interleukine-1β. Pro-apoptotic Bax protein, myeloperoxidase (MPO) and expression of PCNA significantly increased in colonic tissue. Lipid peroxidation (MDA) significantly elevated while reduced glutathione (GSH) was depleted in UC non-treated group compared with normal control group. Treatment with Olmesartan (5 mg, 10 mg/kg/day, orally) ameliorated mucosal ulceration and improved inflammatory signs as confirmed by immunohistochemical and histopathological examination. Also, Olmesartan significantly attenuates overexpression of PCNA in colonic mucosa. Conclusions: Our results point out that Olmesartan had ameliorative effects on UC by its anti-inflammatory, antioxidant and anti-apoptotic effects and attenuates PCNA expression which is the main cause of dysplasia and colorectal cancer. Olmesartan may be a promising therapeutic drug for treating UC and protection of colorectal carcinoma.