Objective To evaluate the cardioprotective effects of silymarin on mice with acute myocardial infarction (AMI) and its possible mechanism. Methods A total of 60 male C57BL/6 mice were randomly divided into 4 groups: Sham group, AMI group, AMI+Silymarin group, and AMI+Vehicle group. Drug administration was started at the second day after modeling and lasted for four weeks. Four weeks after modeling, hemodynamic parameters and quantitative echocardiographic assessments were obtained to evaluate the cardiac function. Myocardium infarct area was estimated by H-E staining. Cell apoptosis was observed by TUNEL and apoptotic index was calculated. Protein expressions of Bcl-2, Bax and Cleaved Caspase-3 were detected by Western blotting analysis. Results Compared with AMI group, AMI+Silymarin group had improved hemodynamic parameters and cardiac function, significantly reduced infarction area and histopathology changes of the infarcted area (P<0.05), significantly decreased cardiomyocyte apoptotic index (P<0.05), significantly increased protein expression of Bcl-2 and significantly decreased expression of Bax and Cleaved Caspase-3 (P<0.05). Conclusion Silymarin can reduce infarction area and improve cardiac function in mice, which might be related to inhibition of the myocardial apoptosis.