Background and Objectives:Urticadioica, a source of bioactive functional compounds, provides nutritional and gastrointestinal therapeutic benefits.The recent study attempted to investigate the prophylactic coloprotective action of aqueous extract of Urticadioica (AEUD) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Materials and Methods: Phenolic compounds, total sugar, and mineral levels were determined in AEUD. Then, AEUD at different doses (50, 100, and 200 mg/kg, BW, p.o.) and Mesalazine (MESA), as a standard treatment (100 mg/kg, BW, p.o.), were given orally for 21 days. Acute colitis was induced by administering drinking water with 5% (w/v) DSS for 7 days. Body weight variation, fecal occult blood, and stool consistency were determined daily. The severity of colitis was graded by colon length, disease activity index (DAI), histological evaluations, and biochemical alterations. Rats orally administered with DSS regularly developed clinical and macroscopic signs of colitis.Results: Due to its richness in phenolic and flavonoid compounds (247.65±2.69 mg EAG/g MS and 34.08±0.53 mg EQt/g MS, respectively),AEUD markedly ameliorated DAI, ulcer scores, colon length shortening, colonic histopathological changes, and hematological and biochemical modifications. Taken together, AEUD-treatment suppressed notably (p< .01) DSS-induced UC by reducing oxidative stress via lowering MDA/H2O2 generation and stimulating effect of enzyme antioxidants as well as attenuating inflammation by decreasing CRP levels by 79.5% between DSS and DSS+AEUD-50 groups compared to MESA-group (75.6%).Conclusions: AEUD was sufficient to exert its coloprotectiveeffect which might be influenced by its bioactive compounds’ anti-inflammatory and antioxidant capabilities.