Piceatannol (3,5,3′,4′-tetrahydroxy-trans-stilbene; PIC) is a polyphenol found in grapes. It is known as a protein kinase inhibitor that modifies multiple cellular targets, exerting immunosuppressive and antitumorigenic activities in several cell lines. The purpose of the present work was to evaluate the anti-inflammatory effect of PIC on dextran sulfate sodium (DSS)-induced colitis. Experimental colitis was induced in BALB/c mice by dissolving 5% DSS in their drinking water for 7 days. PIC (1, 2.5, 5, or 10 mg/kg body weight) was administrated daily per oral route for 7 days. A significant blunting of weight loss and clinical signs was observed in DSS-exposed, PIC-treated mice when compared to vehicle-treated mice. This was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity, and a decrease in production of inflammatory mediators such as nitric oxide (NO), prostaglandin (PG) E2, and pro-inflammatory cytokines. The present data indicate that further evaluation of the potential of PIC as an agent for the prevention and/or treatment of inflammatory bowel diseases in human clinical studies is warranted.