Dyslipidemia has become a critical global issue for public health, with elevating prevalence and morbidity closely related to many cardiovascular diseases (CVD) with high incidence rates. Crataegi Folium (known as Shanzhaye in China, SZ, the leaves of Crataegus pinnatifida Bge. var. major N.E. Br. or Crataegus pinnatifida Bge) and Alisma rhizoma (known as Zexie in China, ZX, the dried tuber of Alisma orientale (Sam.) Juzep or Alisma plantago-aquatica Linn), a classic combination of herbs, have been widely used to treat dyslipidemia. However, the therapeutic mechanism of this pair still remains unclear. Hence, this study aimed to elucidate the molecular mechanism of the Shanzhaye-Zexie herb pair (SZHP) in the treatment of dyslipidemia with the use of a network pharmacology analysis approach.Active compounds, targets of the SZHP, and targets for dyslipidemia were screened based on the public database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed on the database for annotation, visualization, and integrated discovery (DAVID 6.8). The compound-target-disease-pathway network was visualized using the Cytoscape software, and SYBYL was used for molecular docking.Twelve active compounds in the SZHP were screened out, which were closely connected to 186 dyslipidemia-related targets. The network analysis revealed that sitosterol, stigmasterol, isorhamnetin, kaempferol, and quercetin might be candidate agents and CCND1, CASP3, HIF1A, and ESR1 genes were potential drug targets. GO analysis revealed 856 biological processes (BP), 139 molecular functions (MF), and 89 cellular components (CC). The KEGG pathway enrichment analysis indicated that the lipid level and atherosclerosis might influence the treatment of dyslipidemia. Molecular docking showed that quercetin bound well to CCND1, HIF1A, MYC, AKT1, and EGFR genes. These findings were in accord with the prediction obtained through the network pharmacology approach.This study revealed the primary pharmacological effects and relevant mechanisms of the SZHP in treating dyslipidemia. Our findings may facilitate the development of the SZHP or its active compounds as an alternative therapy for dyslipidemia. Still, more pharmacological experiments are needed for verification.Copyright © 2022 Hui Wang et al.