Although Tongguan capsule (TGC) is used in the treatment of coronary atherosclerotic disease, the exact mechanism remains unclear.Network pharmacology and experimental validation were applied to examine the mechanism of TGC for treating myocardial ischemia-reperfusion injury (MIRI).The components and candidate targets were searched based on various databases such as TCMSP, TCMID, BATMAN-TCM. The binding ability was determined by molecular docking. The ischemia-reperfusion (I/R) model was constructed by ligating the left anterior descending (LAD) coronary artery. APOE-/- mice were divided into three groups (n = 6): Sham group, I/R group, and TGC group (1 g/kg/d). To further verification, HCAEC cells were subjected to hypoxia-reoxygenation (H/R) to establish in vitro model.The compounds, such as quercetin, luteolin, tanshinone IIA, kaempferol and bifendate, were obtained after screening. The affinity values of the components with GSK-3β, mTOR, Beclin-1, and LC3 were all <-5 kcal/mol. In vivo, TGC improved LVEF and FS, reducing infarct size. In vitro, Hoechst 33258 staining result showed TGC inhibited apoptosis. Compare with the H/R model, TGC treatment increased the levels of GSK-3β, LC3, and Beclin1, while decreasing the expression of mTOR and p62 (p < 0.05).The findings revealed that TGC exerted a cardioprotective effect by up regulating autophagy-related proteins through the mTOR pathway, which may be a therapeutic option for MIRI. However, there are still some limitations in this research. It is necessary to search more databases to obtain information and further demonstrated through randomized controlled trials for generalization.