Abstract: This study aimed to investigate the inhibitory effect and underlying mechanism of ethanol extract from Chrysanthemum morifolium. 'Boju' (CME) on atherosclerosis (AS). An AS model was established using ApoE⁻/⁻ mice, which were randomly divided into a model group, low-, medium-, and high-dose CME groups (50, 100, and 200 mg/kg), a positive control group (simvastatin 3 mg/kg), and a normal control group, with an intervention period of 12 weeks. The levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in serum, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in serum were measured.. Pathological changes were observed via Oil Red O staining of the aorta and hematoxylin-eosin (H&E) staining of the liver. The expressions of LXRα and ABCA1 in liver tissue and NF-κB p65 in the aorta were detected by qRT-PCR and Western blot. In in vitro experiments, a foam cell model was established by inducing RAW264.7 macrophages with ox-LDL, and the cells were divided into a control group, a model group, and low-, medium-, and high-dose CME groups (25, 50, and 100 μg/mL). Cell viability, foam cell rate, intracellular contents of TC, cholesteryl ester (CE), and free cholesterol (FC), as well as the expressions of genes and proteins related to relevant signaling pathways were detected. Additionally, the NF-κB inhibitor BAY11-7082 was used to verify the mechanism. The results showed that compared with the model group, CME significantly decreased the serum levels of TC, TG, and LDL-C, and increased the serum level of HDL-C (P<0.01). Pathological staining demonstrated that the low-, medium-, and high-dose CME groups could reduce aortic lipid deposition and hepatic steatosis in a dose-dependent manner. Furthermore, CME significantly upregulated the mRNA and protein expressions of LXRα and ABCA1 in liver tissue (P<0.01), with the protein level of LXRα upregulated from 0.31±0.04 in the model group to 0.91±0.06 in the high-dose CME group. In addition, CME reduced the protein expression of p-NF-κB p65 in the aorta and the serum levels of TNF-α, IL-6, and IL-1β (P<0.01), and the protein level of p-NF-κB p65 decreased from 1.85±0.18 in the model group to 0.92±0.11 in the high-dose CME group. Meanwhile, CME decreased the intracellular contents of TC and CE and the CE/TC ratio in RAW264.7 macrophages, thereby inhibiting foam cell formation. Moreover, it upregulated the expressions of PPARγ, LXRα, and ABCA1 and inhibited the activation of the NF-κB pathway, and no significant differences were observed in key indicators such as p-NF-κB p65, ABCA1, TC, CE, and CE/TC ratio between the high-dose CME group and the BAY11-7082 inhibitor group. These results indicated that AS could be significantly inhibited by CME through activating the LXRα/ABCA1 pathway to regulate cholesterol metabolism and inhibiting the NF-κB pathway to alleviate inflammatory responses.