Background: despite its vast utility in clinical oncology, the use of doxorubicin is limited by a potentially fatal cardiomyopathy and congestive heart failure. Free radical formation and antioxidants depletion are mechanisms proposed for this cardiomyopathy. The aim of this study is to compare the potential antioxidative protective effect of silymarin on doxorubicin-induced cardiotoxicity in experimental mice. Materials and methods: four groups (ten animals in each group) of experimental mice were used as follows: Group 1, mice received only saline (intraperitoneally) and served as a negative control group; Group 2, mice received doxorubicin (intraperitoneally, 5 mg/kg body weight) in three equal injections over a period of two weeks for a cumulative dose of 15 mg/kg body weight; Group 3, mice orally administrated silymarin (200 mg/day/kg body weight) respectively, through an intragastric feeding tube over a period of three weeks; Group 4, mice treated orally with silymarin plus intraperitoneally doxorubicin administration with the same protocol of groups 3 and 4. Serum lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), malondialdehyde (MDA), total nitric oxide (NO), cardiac reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were measured in all tested groups. Results: doxorubicin elevated the activities of LDH, CPK, AST, ALT, MDA and NO in the cardiac tissue. Cardiac antioxidant enzymes activities SOD and CAT also increased while GPx activity was decreased. Pre-co-treatment with silymarin prevented the changes induced by doxorubicin administration. These findings demonstrate the cardio-protective effect of silymarin on cardiac antioxidant status during doxorubicin induced cardiac damage in mice. Conclusion: silymarin could be recommended for further investigation as potentially new indication for clinical application.