Background: The traditional Chinese medicine Shuxin Shengmai Dan (SXSMD) is clinically used to treat angina pectoris. The mechanism of action of SXSMD protection of the heart involves inhibition of inflammation and remains poorly understood. The role of SXSMD in rats with myocardial ischemia reperfusion (IR) and the mechanism of SXSMD action were studied in this research.Methods: The rats were treated with SXSMD (3.38, 6.76, and 13.52 g/kg/day, p.o.) or Danshen injecta (1.8 mL/kg/day, p.o.) for 15 days, then the coronary arteries were ligated. Cardiac function was evaluated by electrocardiography and hemodynamic measurements. Hematoxylin-eosin (H&E) staining was used to detect pathological changes in ischemic myocardial sections. Transmission electron microscopy (TEM) was used to assess the ultrastructure of cardiomyocytes. The changes in IL-6 and TNF-α in the rat serum were detected by ELISA. The changes in the expression levels of HMGB1, TLR4, MyD88, and NF-κB mRNAs and proteins related to the TLR4/NF-κB pathway in myocardial tissue were detected by qPCR and Western blot, respectively.Results: Rats with coronary artery ligation had abnormal cardiac function, inflammatory infiltration of myocardial cells, disordered myocardial fiber arrangement, accumulation of mitochondria, and disordered muscle fibers and sarcomeres according to electron microscopy. The levels of the expression of mRNAs and proteins in myocardial tissue of the SXSMD group were decreased compared with those in the MIRI group. The serum levels of IL-6 and TNF-α were decreased. SXSMD treatment can inhibit the inflammatory response and downregulate the TLR4/NF-κB pathway in cardiomyocytes.Conclusion: SXSMD protects the rats from myocardial ischemia-reperfusion injury in the MIRI model by downregulating the TLR4/NF-κB pathway to inhibit inflammation.