Abstract: The effects of local myocardial administration of lactic acid and low-dose edaravone were investigated to determine if this combination provides benefits similar to mechanical postconditioning. We randomly divided 108 rats into 6 groups: sham, reperfusion injury, postconditioning (Post), lactic acid (Lac), low-dose edaravone (Eda), and lactic acid + low-dose edaravone (Lac+Eda). The left coronary arteries of the rats were occluded for 45 minutes, before the administration of the treatments. The rats were euthanized at different time points to examine the infarct size and serum markers of myocardial injury and apoptosis and measure the expression of signal pathway markers. We found that the infarct areas caused by ischemic–reperfusion injury were reduced largely by postconditioning and Lac+Eda injection; a similar trend was observed for serum markers of myocardial injury, apoptosis, and hemodynamic parameters. Compared with the Post group, the Lac+Eda group had similar blood pH values, levels of reactive oxygen species, mitochondrial absorbance, and levels of signal pathway marker. The Lac and Eda groups partly mimicked the protective role. These data suggest that local myocardial administration of lactic acid and low dose of edaravone initiates protective signal pathways of mechanical postconditioning and replicates the myocardial protection.