BACKGROUND: This study aimed to analyze the advantageous effects of the decoction aqueous extract of Arbutus unedo fruits (AUFDE) against ulcerative colitis (UC) caused by acetic acid (AA) in rats, along with the processes involved in this protective effect. Adult male Wistar rats were divided into six groups: control (H(2)O), AA, AA combined with various doses of AUFDE (75, 150, and 300 mg kg(-1) b.w., p.o.), and AA combined with sulfasalazine (SULF) (100 mg kg(-1) b.w., p.o.) during 7 days. All rats underwent overnight fasting, followed by the induction of UC via rectal infusion of AA (300 mg kg(-1) b.w.) at a concentration of 3% (v/v), administered at a volume of 5 mL kg(-1) b.w. for 30 s. The colon was resected and subjected to macroscopic examination to assess ulcerated areas and the ulcer index. RESULTS: The in vivo assay's findings revealed that AUFDE pretreatment attenuates histological changes and significantly reduces colonic mucosa lesions caused by AA. Also, AUFDE reduced the oxidative state that AA caused in the colonic mucosa, as indicated by elevated malondialdehyde levels and the reduction of both enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase, and non-enzymatic antioxidants such as thiol groups. Furthermore, AUFDE pretreatment controlled the dysregulation of all intracellular mediators and significantly decreased inflammatory indicators like C-reactive protein and alkaline phosphatase levels, whereas AA intoxication raised iron and calcium levels in plasma. According to our findings, AUFDE may have protected rats from AA-induced colitis. (c) 2025 Society of Chemical Industry.