Abstract: Objective To investigate the mechanism by which Shexiang Tongxin dripping pills (STDP) improves coronary microcirculation disorder (CMD) and cardiac dysfunction in a porcine model of myocardial ischemia-reperfusion injury. Methods Fourteen minipigs were randomly selected for interventional balloon occlusion of the middle left anterior descending branch to induce CMD, and another 7 pigs received sham operation. The pig models of CMD were randomized equally into the model group and STDP-treated group. All the animals were fed with common feed for 8 weeks, and in STDP-treated group, the pigs were given STDP at the daily dose of 3 mg/kg (mixed with feed) for 8 weeks. Before and at the 8th week after the operation, the pigs underwent coronary angiography and echocardiography to determine the vessel lumen diameter and TIMI frame count (CTFC). The pathologies of the myocardium and the microvessels were examined with HE staining at the 8th week. Western blotting was used to detect the expression of silencing information regulator (Sirt1), peroxidase proliferator-activated receptor-γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), extracellular signal-regulated kinase1/2 (ERKI/2), Toll-like receptor 4 (TLR4), and uncoupling protein 2 (UCP2) in myocardial tissue. Results Before and at the 8th week after the operation, the diameter of the anterior descending vessel in the 3 groups did not differ significantly (P>0.05). At the 8th week, the number of CTFC frames in the model group increased significantly compared with that in the sham-operated group, but was obviously lowered by treatment with STDP (P<0.05). Myocardial ischemia-reperfusion injury significantly increased the interventricular septal thickness at end-diastole, left ventricular end-diastole dimension, end-diastole volume, interventricular septal thickness at end-systole and left ventricular mass at 8 weeks after the modeling (P<0.05), but such changes were significantly alleviated by treatment with STDP (P<0.05). STDP treatment markedly alleviated myocardial microvascular congestion, thrombosis and peripheral inflammatory cell infiltration induced by myocardial ischemia-reperfusion, but atrophy of the myocardial muscle fiber remained distinct. STDP obviously suppressed the down-regulation of Sirt1, PGC-1α, and PPARα and the up-regulation of ERK1/ 2, TLR4, and UCP2 in the myocardial tissues induced by myocardial ischemia-reperfusion injury. Conclusion STDP has anti-inflammatory effects and regulates energy metabolism in the myocardium through modulating Sirt1, PGC-1α, PPARα, ERKI/2, TLR4, and UCP2 to improve CMD and cardiac dysfunction after myocardial ischemia-reperfusion.