BACKGROUND: Tongmai Yangxin Pills (TMYXP) is a well-known traditional Chinese medicine compound to treat coronary heart disease (CHD). Aging is a key immutable independent risk factor for CHD. Currently, there are few gene expression profiles of patients treated with traditional Chinese medicine (TCM) or TCM compound. However, the chemical composition and underlying mechanisms of TMYXP against elderly CHD need to be elucidated. OBJECTIVE: Exploring the mechanism of TMYXP in treating elderly CHD based on human gene expression profiles, and find the key pharmacodynamic ingredients of TMYXP in treating elderly CHD based on plasma pharmacochemistry and network pharmacology. METHODS: A strength of this study is the use of network pharmacology analysis of gene expression profiles in elderly CHD patients before and after TMYXP treatment. This study focused on peripheral blood mononuclear cell samples from 6 elderly patients with CHD over 60 years old (GSE142008). A total of 40 blood components of TMYXP identified by UPLC/Q-TOF-MS method in the plasma of SD rats. Then, we collected literature-validated TMYXP blood component targets for further network pharmacology analysis. RESULTS: All blood components of TMYXP exhibited non-toxic properties. By retrieving validated TMYXP blood components's targets, 15 blood components correspond to a total of 4,789 targets. Genistein, emodin, isoliquiritigenin, glycyrrhizic acid, gallic acid, verbascoside, calycosin, rhein, formononetin and ephedrine were the most potential anti-CHD blood components in TMYXP. The above 10 key blood components of TMYXP mainly regulate hub genes CONCLUSION: This study builds a bridge connecting TMYXP blood components and its confirmed clinical efficacy, identifies a series of anti-CHD lead compounds, and analyzes their possible mechanisms for treating CHD. The research strategy of this study has the potential to promote the modernization and transformation of TCM and promote the drug development.