Shixiao powder comes from the Formularies of the Bureau of People’s Welfare Pharmacies in the Song Dynasty and consists of two herbs, Puhuang (PH) and Wulingzhi (WLZ). PH-WLZ is a commonly used drug pair for the treatment of coronary heart disease (CHD), and its clinical effect is remarkable. However, our understanding of the mechanism of treatment of CHD is still unclear. In this study, the method of network pharmacology was used to explore the mechanism of PH-WLZ in the treatment of CHD. A total of 56 active ingredients were identified from PH-WLZ, of which 93 targets of 41 active ingredients overlapped with those of CHD. By performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we obtained the main pathways associated with CHD and those associated with the mechanism of PH-WLZ in the treatment of CHD. By constructing the protein-protein interaction (PPI) network of common targets, 10 hub genes were identified. Based on the number of hub genes contained in the enrichment analysis, we obtained the key pathways of PH-WLZ in the treatment of CHD. The key KEGG pathway in the treatment of CHD by PH-WLZ is mainly enriched in atherosclerosis, inflammation, immunity, oxidative stress, and infection-related pathways. Moreover, the results of molecular docking showed that the active ingredients of PH-WLZ had a good affinity with the hub genes. The results indicate that the mechanism of PH-WLZ in the treatment of CHD may be related to regulation of lipid metabolism, regulation of immune and inflammatory responses, regulation of downstream genes of fluid shear stress, antiaging and oxidative stress, and virus inhibition.