: This study aimed to evaluate the therapeutic effects of Gualou Xiebai Banxia Decoction (GXBD) on atherosclerosis (AS) in a mouse model and to explore its underlying mechanisms. Male APOE-/- mice were used to induce the AS model through a 16-week high-fat diet. The mice were randomly divided into a model group, a control group, different dosage groups of GXBD, and a lipid-lowering drug group. Histological analysis using HE and Oil Red O staining was performed to observe changes in arterial walls and plaque formation. The results demonstrated that GXBD significantly reduced plaque formation. Further miRNA sequencing analysis revealed that GXBD regulated multiple AS-related miRNA genes, influencing the expression of key proteins such as Epsin1 and FGFR1, thereby exerting potential therapeutic effects on AS lesions. Western blot and immunofluorescence experiments further validated these regulatory effects. The findings suggest that GXBD exhibits significant efficacy in the treatment of atherosclerosis, potentially through miRNA regulation and protein expression modulation.