Background Ulcerative colitis (UC) is a global inflammatory bowel disease. Aime :This study aimed to assess the effects of icosapent ethyl on acetic acid-induced colitis in rats as well as the underlying mechanisms involved. Methods 36 male Wister rats were equally divided into Six groups: control, UC, mesalamine 100 mg/kg, icosapent 150mg/kg, icosapent 300 mg/kg, and EX527-icosapent 300 mg/kg groups. EXcept for control group, UC was induced by acetic acid instillation into colon. Drugs were administered once daily for one week then under thiopental anaesthesia, colons were excised. Colitis macroscopic and microscopic scores were assessed. A part of colon was homogenized for detection of malondialdehyde (MDA), inerleukin1 (IL-1β), tumor necrosis factor (TNF-α), superoxide dis-mutase (SOD), phosphorylated Akt (pAkt) and caspase 3 levels. Silent information regulator 1 (SIRT1), hemeoxygenase 1 (HO-1), and nuclear factor erythroid 2 (Nrf2) mRNA expressions were detected. Mallory-stained colonic sections were examined for collagen fibres detection. Immunohistochemistry of NF-κB and p53 expressions in colonic sections were assessed. Results There acetic acid induced colitis increments in MDA, IL-1β, TNF-α, and caspase 3 levels while decreased SOD, pAkt, SIRT1, HO-1, and Nrf2 with increased collagen fibres as well as NF- κB and p53. Icosapent decreased macro& microscopic colitis scores, MDA, IL-1β, TNF-α, and caspase 3 levels while increased SOD, pAkt, SIRT1, HO-1, and Nrf2 with decreased collagen fibres as well as NF-κB and p53. The effects of icosapent 300 mg/kg were similar to mesalamine. Icosapent effects were antagonized by EX527. Conclusion Icosapent alleviated acetic acid-induced colitis via its anti-inflammatory, Antioxidant, and anti-apoptotic effects mediated in part by SIRT1 pathway activation