Background: Different studies have been done on Hypericum anti-depressant effects, but only a few ones have documented in vivo anti-inflammatory properties of Hypericum following systemic administration. Objectives: This survey was designed to evaluate the potential effects of Hypiran, a hydro-alcoholic extract of St. John's Wort, for the treatment and controlling inflammation in animal models of ulcerative colitis. Methods: In this experimental study, ulcerative colitis was induced in the male Wistar rats by luminal instillation of acetic acid. Animals in the treatment groups received Hypiran (150 mg/kg PO) or Prednisolone (4 mg/kg PO) daily for 10 consecutive days. At the end, the rats were sacrificed and the disease activity index, the levels of malondialdehyde, myeloperoxidase, nitric oxide, total protein and the concentration of TNF-α, IL-1β and IL-6 were assessed in the colonic homogenized tissue specimens. Results:The results showed that both therapies with Hypiran and Prednisolone could regress the clinical scores and the mortality rate of ulcerative colitis in a comparable manner. The levels of TNF-α, IL-1β and myeloperoxidase activity were down-regulated in the guts of Prednisolone treated rats more than Hypiran groups. Nevertheless, Hypiran decreased the levels of IL-6, nitric oxide and malondialdehyde more significantly than Prednisolone. Conclusions: Collectively, these data suggest that the Hypiran may be used as a natural source to alleviate the signs of rat model of ulcerative colitis.