Background: Coronary heart disease (CHD) is a chronic cardiovascular disease across the world, which poses numerous threats to mankind. Wuwei Yuganzi San (WYS) is a famous traditional Tibetan medicine prescription. It has been confirmed effective in the treatment of CHD, but its specific mechanism remains still unclear. Objective: To elucidate the main pharmacological action of WYS in treating CHD and investigate the underlying multiple mechanisms of its multi-ingredient-multi-target by network pharmacology.Methods: Firstly, active ingredients of WYS and connected targets of five herbs were retrieved by using traditional Chinese medicine systems pharmacology (TCMSP) and screening literature. Then, genome explanation databases (OMIM and GeneCards) were used to acquire targets related to CHD. The protein-protein interaction (PPI) network was built using the mutual targets filtering genes through protein interaction. Next, a network diagram could be established with the help of Cytoscape 3.8.2. And, STRING platform was used to construct a protein interaction network. Finally, GO and KEGG analyses were analyzed to further elucidate biological process enrichment.Results: After the screening, 36 active ingredients and 202 related targets in WYS in addition to 952 disease-related targets were acquired. A total of 37 key targets including AKT1, ESR1, and EGFR were screened in the PPI network. These targets were mostly concentrated on the transmembrane receptor protein tyrosine kinase signaling pathway, cellular response to growth factors stimulus, and response to growth factor. The KEGG enrichment demonstrated that the MAPK signaling pathway, P13K/AKT signaling pathway, Ras signaling pathway, and other corresponding signaling pathways were closely related to CHD.Conclusions. WYS plays a significant role in the treatment of CHD. And this study provides a novel approach to disclose the therapeutic mechanisms of WYS on CHD.