Background: Recent studies have identified the involvement of the inflammatory pathway and the oxidative stress pathway in the pathogenesis of ulcerative colitis. Objectives of the study: to investigate the weight loss, colon weight to length ratio, and histological improvement in a mouse model of acetic acid -induced colitis received a preventive melatonin. Materials and methods: 48 mice were divided into 4 groups (n =12): group A: normal group; group B: control group; group C: melatonin pretreatment group at a 100 mg/kg; group D: mice were treated with mesalamine as a reference drug for ulcerative colitis. Ulcerative colitis was induced intrarectal administration of 2 ml 6% (v/v) AA in 0.9% NaCl using a soft cannula. Colitis was induced in the seventh day of experiment and finally all mice were killed in the eightieth day under deep ether anaesthesia. Results: The highest value of weight loss improvement was recoded in group C (4.29%) with no significant differences between treatment and protective groups (p > 0.05). Additionally, the colon weight to length ratio recorded for treatment and protective groups were not significantly differ between each other (p>0.05). Histological examination showed that melatonin with 100 mg/kg dose reduced the depth of ulcers (1.000±1.14), without a statistically significant difference with mesalamine group (0.375±0.740). Conclusion: The protective effect of melatonin against ulcerative colitis induced in mice was demonstrated. Melatonin alleviated the symptoms of ulcerative colitis, the weight loss in ulcerative colitis was limited. Moreover, colon weight/length ratio and histological parameters improved. KEYWORDS: Ulcerative colitis – Intestinal – Melatonin