BACKGROUND: Atherosclerosis (AS), which causes chronic inflammation, aberrant lipid metabolism and vascular endothelial damage, is the main cause of cardiovascular disease. The Ce-Bai-Si-Wei decoction (CSD) may reduce AS, although its molecular mechanisms are unknown. This study investigates core molecular pathways using multi-omics integration and experimental validation. METHOD: Network pharmacology prediction: Construct a 'drug-component-target-disease' interaction network using databases like TCMSP, HIT and ETCM to identify active components and targets of CSD. AS regulatory targets and signalling pathways can be identified by integrating microarray data and single-cell transcriptomics data. In vitro validation: Utilise the OX-LDL-induced model of macrophage foam cells to test CSD's effects on lipid accumulation utilising CCK-8, Oil Red O and TC/TG quantification. Validate CSD's regulatory effects on core targets using molecular docking, molecular dynamics simulation, RT-qPCR and Western blot. RESULTS: Four core genes, HMOX1, SELE, CD4 and FLT1, were identified as key regulators of inflammation and oxidative stress in AS, and they bind stably to the active components of CSD. Single-cell data analysis suggested that CSD may improve AS by targeting macrophages and endothelial cells. In vitro, CSD reduced ox-LDL-induced lipid accumulation in macrophages and downregulated TNF-α and IL-1β. Mechanistically, the anti-AS effect of CSD depends on the NRF2/HMOX1 pathway. CSD also downregulated FLT1 and SELE in damaged endothelial cells. CONCLUSION: This study investigated the mechanism of CSD in treating AS. CSD acts on the core targets HMOX1, SELE, FLT1 and CD4, with macrophages and endothelial cells as key effector cells. It exerts anti-AS effects by inhibiting inflammation, reducing lipid accumulation and protecting endothelial function.