Network pharmacology was utilized to predict the key targets and mechanism of action of Wen Dan Decoction (WDD) in treating atherosclerosis (AS) and conducted preliminary experimental validation. Initially, overlapping targets of WDD and AS were screened using databases such as TCMSP, SYMmap, and GeneCards. Subsequently, protein-protein interaction (PPI) analysis, along with gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses, suggested that tumor protein p53 (TP53), protein kinase B1 (AKT1), signal transducer and activator of transcription 3 (STAT3), and interleukin-6 (IL-6) were the core targets. The mechanisms involved pathways related to anti-oxidative stress, lipid metabolism, tumor necrosis factor-α (TNF-α) signaling, and the p53 signaling pathway. An AS model was then replicated in ApoE^-/- mice fed a high-fat diet. After intervention with WDD, experimental assessments including HE staining, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting (WB) were performed to measure four blood lipid parameters, oxidative stress-related indicators, and the protein and gene expression levels of p53, solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). The experimental results show that WDD reduces the plaque area in the aorta of ApoE^-/- model mice, decreases total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) levels, lowers serum superoxide dismutase (SOD) and glutathione (GSH) levels while increasing malondialdehyde (MDA) levels, downregulates the mRNA and protein expression levels of p53, and upregulates the mRNA and protein expression levels of SLC7A11 and GPX4. It can be seen that WDD can combat AS by regulating lipid metabolism, exerting anti-oxidative stress effects, and inhibiting ferroptosis. Its mechanism of action is likely associated with the modulation of the p53 signaling pathway.