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This study aimed to investigate the therapeutic effects of Jiangzhi Huaban Decoction(JZHB) on atherosclerosis(AS) model mice and to explore its potential molecular mechanisms using proteomic analysis. C57BL/6J mice fed with a standard diet served as the control group. ApoE~(-/-) knockout mice were fed with a high-fat diet for 8 weeks to induce atherosclerosis, after which they were randomly divided into 5 groups(n=8 per group): the model group, low-, medium-, and high-dose JZHB groups(1.32, 2.64, and 5.28 g·kg~(-1)), and the atorvastatin calcium group(3.75 mg·kg~(-1)). All intervention groups lasted for 8 weeks. The body weight and general conditions of the mice were recorded weekly. Prior to sample collection, small animal color Doppler ultrasound was employed to assess carotid artery and aortic wall plague lesions. After sample collection, serum lipid and liver function levels were measured using an automated biochemical analyzer. Serum levels of interleukin(IL)-6, IL-1β, IL-4, and tumor necrosis factor-alpha(TNF-α) were quantified by enzyme-linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining. Masson and oil red O staining were used to comprehensively evaluate pathological changes in AS plaques. Proteomics sequencing technology was used to analyze core molecular mechanisms, and Western blot, qPCR, and immunofluorescence assays were used to verify the expression of core targets. The results showed that JZHB significantly improved serum lipid levels, liver function, and serum inflammatory microenvironment in AS mice(P<0.05, P<0.01). It can also comprehensively improved various pathological markers, including carotid artery and aortic root plaque area, collagen fiber content, lipid deposition, lumen stenosis, and hemorheological parameters(P<0.05, P<0.01). Proteomics analysis revealed that its core mechanism was associated with the mitogen-activated protein kinase(MAPK)/nuclear factor-κB(NF-κB) signaling pathway axis to improve macrophage polarization in AS plaques. Molecular biological assays indicated that JZHB could reduce the mRNA levels and the phosphorylation ratios of MAPK, c-Jun N-terminal kinase(JNK), NF-κB p65, and inhibitor of nuclear factor-κBα(IκBα) in the aortic tissue of mice. It also downregulated the mRNA and protein expressions of inducible nitric oxide synthase(iNOS) and IL-6(P<0.05, P<0.01). Additionally, JZHB improved the expression and localization of M1/M2 macrophage polarization markers, cluster of differentiation 86(CD86) and mannose receptor(CD206), within aortic plaques(P<0.05, P<0.01). In conclusion, JZHB can synergistically ameliorate the pathological changes in arterial plaques of AS mice through multiple pathways. Its core mechanism involves regulating the MAPK/NF-κB signaling pathway axis, ameliorating the macrophage polarization status and the internal inflammatory microenvironment within plaques, thereby exerting a comprehensive pharmacological effect on the prevention and treatment of atherosclerosis.