Introduction: The management of ulcerative colitis (UC) depends on establishing novel alternate approaches that might minimize intestinal inflammation. Omega 3 and Pioglitazone has been found to suppress pro-inflammatory pathways via activating peroxisome proliferator activated receptor-γ (PPARγ). Aim of the Work: The research effort attempted to assess the impact of omega 3 and pioglitazone on acute colitis which is experimentally triggered by dextran sodium sulphate (DSS) in rats. Material and Methods: In the current work four distinct groups of 42 adult healthy male albino rats were established in the following order: Group I (normal control group). Group II (DSS group): got 5% DSS via oral gavage daily for the first seven days, then followed by 3% DSS daily for the subsequent seven days. Group III (DSS+ PIO group): Rats recieved pioglitazone at daily dose of 10 mg/kg. Pioglitazone was dissolved in 0.9% NaCl via oral gavage for a total of 14 days consecutively commenced with the first day of DSS administration and proceeded until the completion of the study. Group IV (DSS+OMEGA3 group): Rats got omega 3 daily at a dose of 300 mg/kg via intragastric intubation for 14 days commenced with the first day of DSS administration and ending at the completion of the trial. Two weeks since the start of the study, rats were sacrificed then colon specimens were obtained, processed and evaluated using histological and immunohistochemical techniques. Results: The DSS-induced colitis group displayed colonic epithelial erosions, inflammatory infiltration of the lamina propria, dilated and destructed intestinal crypts, mucin depletion, and goblet cell structural distortion. Group III exhibited improvement of these changes, whereas Group IV showed amelioration of the majority of these changes. Conclusion: Omega 3 and pioglitazone mitigated most pathological alterations in DSS induced colitis.