Aim To explore the effect of paeonol (Pae) on the FXR-FGF15 signaling pathway by regulating the metabolism of bile acids in ApoE－/－ mice, thereby affecting lipid metabolism to play an anti-atherosclerotic effect. Methods ApoE－/－ mice were fed high-fat diet for 20 weeks to establish an atherosclerotic plaque model, and the model was created and injected with paeonol (200 mg/kg). Oil red O staining was used to observe the pathomorphological changes of the aorta and liver tissues; Enzymatic method was used to detect the lipid levels of blood and liver; LC-MS/MS was used to detect changes in mouse intestinal bile acid composition; Western blot was used to detect the expression of mouse liver CYP7A1, ileum FXR and FGF15. Results Paeonol significantly reduced the plaque area of the aorta in atherosclerotic model mice and reduced lipid deposition in the liver; significantly reduced the levels of triglyceride, total cholesterol and liver coefficient in serum and liver; increased the content of FXR antagonists TαMCA and TβMCA, reduced the content of FXR agonists CDCA and LCA, inhibited the intestinal FXR-FGF15 signaling pathway, induced the expression of CYP7A1 protein in liver tissue, and increased the efflux of total bile acid in feces. Conclusion Paeonol may affect the metabolism of bile acids and inhibit the FXR-FGF15 axis to promote the synthesis and excretion of bile acids in the liver, reduce cholesterol accumulation, and achieve its anti-atherosclerotic effect.