Background: Myocardial infarction (MI), characterized by reduced blood flow to the heart, is a coronary artery disorder with the highest morbidity and mortality among cardiovascular diseases. Consequently, there is an urgent need to identify effective drugs to treat MI. Rhizoma Corydalis (RC) is the dry tuber of Corydalis yanhusuo W.T. Wang, and is extensively applied in treating MI clinically in China. Its underlying pharmacological mechanism remains unknown. This study aims to clarify the molecular mechanism of RC on MI by utilizing network pharmacology and experimental verification.Methods: Based on network pharmacology, the potential targets of the RC ingredients and MI-related targets were collected from the databases. Furthermore, core targets of RC on MI were identified by the protein-protein interaction (PPI) network and analyzed with Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was used to validate the binding affinity between the core targets and the bioactive components. Oxygen-glucose deprivation (OGD) was performed on H9c2 cells to mimic MI in vitro. A Cell Counting Kit-8 assay was used to assess the cardioprotective effect of the active ingredient against OGD. Western blot analysis and RT-qPCR were used to measure the cell apoptosis and inflammation level of H9c2 cells.Results: The network pharmacology obtained 60 bioactive components of RC, 431 potential targets, and 1131 MI-related targets. In total, 126 core targets were screened according to topological analysis. KEGG results showed that RC was closely related to the phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (PKB, also called Akt) signaling pathway. The experimental validation data showed that tetrahydropalmatine (THP) pretreatment preserved cell viability after OGD exposure. THP suppressed cardiomyocyte apoptosis and inflammation induced by OGD, while LY294002 blocked the inhibition effect of THP on OGD-induced H9c2 cell injury. Moreover, the molecular docking results indicated that THP had the strongest binding affinity with Akt over berberine, coptisine, palmatine, and quercetin.Conclusion: THP, the active ingredient of RC, can suppress OGD-induced H9c2 cell injury by activating the PI3K/Akt pathway, which in turn provides a scientific basis for a novel strategy for MI therapy and RC application.