As one of the major cardiovascular diseases, myocardial infarction is the most serious manifestation of coronary artery disease, which has attracted wide attention due to its high morbidity and mortality. The left anterior descending artery(LAD) of 6-8 weeks old male KM mice was ligated for 40min, followed by perfusion to establish an ischemia-reperfusion(I/R) model. After 3 days of monitoring, 60 mg/kg sacubitril/valsartan sodium was given for a week. Hematoxylin-eosin(HE) staining, 2, 3, 5-triphenyl-tetrazolium chloride(TTC) staining and echocardiography were used to evaluate the therapeutic effect of sacubitril/valsartan sodium on I/R.The proteomics information of heart tissue was obtained by data-independent acquisition(DIA) proteomics. The analysis results showed that sacubitril/valsartan sodium may mediate the treatment of I/R injury by regulating enzyme activity and immune-related biological processes, up-regulating fatty acid degradation metabolic pathway, PPAR pathway, peroxisome pathway, and down-regulating complement system and ribosome pathway.The results showed that sacubitril/valsartan sodium had a good therapeutic effect on I/R injury.