Inflammatory bowel disease (IBD) is a common and chronic gastrointestinal disorder characterized by intestinal inflammation and mucosal tissue damage. Reactive oxygen metabolites (ROMs) play a pathogenic role in IBD. We aimed to examine the protective effect of sildenafil, a cGMP phosphodiesterase inhibitor, in the experimental mouse model of IBD. Intrarectal instillation of acetic acid was used to induce IBD. Prednisolone was used as the standard drug for comparison. Sildenafil was used at doses of 0.75, 1.5, and 3 mg/kg. Biochemicals and macroscopic and microscopic examinations of colonic tissue were performed. Results indicated that activity of myeloperoxidase (MPO) and lipid peroxidation product (TBARS) markers of oxidative stress are increased in acetic acid-treated groups and are recovered by sildenafil pretreatment and prednisolone. Sildenafil- (1.5 and 3 mg/kg) and prednisolone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared to the acetic acid-treated group. The beneficial effect of sildenafil (3 mg/kg) was comparable to that of prednisolone. It is concluded that sildenafil is helpful in the management of IBD, which is presumably related to its strong antioxidative stress potential mediated through enhanced cGMP. Results of proper clinical trials will determine the possible efficacy of phosphodiesterase-5 inhibitors in human IBD.