Mycophenolate mofetil (MMF) as an immunosuppressive agent is used to prevent graft rejection. One of the adverse effects of long time administration of MMF is the gastrointestinal disorder. This study aimed to investigate the gastroprotective effect of silymarin (SMN) on MMF-induced gastrointestinal (GI) disorders. Twenty-four adult female Wistar rats were assigned into three groups including the control and test groups. The control animals received saline (5 mL kg^-1) and the test animals were treated with MMF (40 mg kg^-1, orally) and saline, MMF and silymarin (SMN, 50 mg kg^-1, orally) for 14 consecutive days, respectively. To evaluate the GI disorders due to the MMF-induced oxidative stress and subsequently the protective effect of SMN, malondialdehyde (MDA), total thiol molecules (TTM) levels and total anti-oxidant capacity (TAC) were determined. Additionally, histopathological examinations in the duodenal region of small intestine were performed. The MMF-increased level of MDA was reduced by SMN administration, while the MMF-reduced level of TTM increased significantly (p < 0.05) by SMN administration. Histopathological examinations showed the goblet cell reduction and congestion in the MMF-received animals; while SMN was able to improve the MMF-induced goblet cell reduction and congestion. Our data suggest that the MMF-induced GI disorders are characterized by changes in antioxidant status, which presented by the elevation of MDA level and reduction of TTM concentration. Moreover, the improved biochemical alterations and histopathologic damages by SMN indicating its gastroprotective and antioxidant effects.