Objective This study aims to evaluate the therapeutic effect of Gualou Xiebai Banxia Decoction (GXBD) on an atherosclerosis (AS) mouse model and explore its underlying mechanism. Methods Male ApoE^-/- mice were fed a high-fat diet for 16 weeks to induce the AS model. Mice were divided into a model group, control group, GXBD treatment groups (at different doses), and a lipid-lowering drug group. Histological assessments (HE and Oil Red staining) were performed to observe arterial changes. MicroRNA (miRNA) sequencing was used to analyze the regulatory effect of GXBD. Western blot and immunofluorescence were applied to confirm key protein expression. Results GXBD significantly reduced plaque formation and regulated several AS-related miRNAs, notably impacting Epsin1 and FGFR1 protein expression. Western blot and immunofluorescence further validated these effects. Conclusions GXBD demonstrated a therapeutic effect on AS by regulating miR-3102-5p, miR-3547-5p, and miR-7080-5p, downregulating Epsin1, and upregulating FGFR1, thereby inhibiting endothelial-to-mesenchymal transition.