Cardiotonic Pills ® (CP) is a compound preparation widely used in China for the treatment of cardiovascular disease. However, limited data is available regarding the mechanism of action of CP on myocardial function during ischemia‐reperfusion (I/R) injury. In this study, we examined the effect of CP on I/R‐induced coronary microcirculatory disturbance and myocardial damage. Male SD rats were subjected to left coronary anterior descending branch occlusion for 30 min followed by reperfusion with or without pre‐treatment with CP (0.1, 0.4, or 0.8 g/kg). Coronary blood flow, vascular diameter, velocity of RBC, and albumin leakage were evaluated in vivo. In parallel, neutrophil expression of CD18, malondialdehyde, and myocardial infarction, endothelial expression of ICAM‐1, apoptosis‐related proteins, histological and ultrastructural of myocardial damage were assessed. Pre‐treatment with CP (0.8 g/kg) attenuated the I/R‐induced myocardial microcirculatory disturbance. In addition, the drug significantly ameliorated the I/R‐induced myocardial damage and apoptosis indicated by increased malondialdehyde, infarct size, myocardial ultrastructural changes, terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling‐positive myocardial cells, and expression of Bcl‐2, Bax and caspase‐3 in myocardial tissues. The results provide evidence for the potential role of CP in preventing microcirculatory disturbance and myocardial damage following I/R injury.