Objective To observe whether the Chinese medicine Xueguan Ruanhua Pill can prevent and treat atherosclerosis（AS）by targeting the regulation of long⁃chain non⁃coding RNA⁃TGFB2⁃OT1，miR4459 and their downstream signals to inhibit inflammatory response. Methods AS model was established；Xueguan Ruanhua Pill was used for intervention，and TGFB2⁃OT1 inhibitor was used as a positive control. After 8 weeks of interven⁃ tion，biochemical detection was performed，HE staining was used to observe the pathological changes of the aorta， and real ⁃time PCR and western ⁃blot were used to detect aortic TGFB2⁃ OT1，miRNA4459，LARP1，SQSTM1， CASP1，and IL1B level. Results Compared with the model group，the level of TC，TG and LDL ⁃C in Fufang Xueguan Ruanhua Pill group decreased（all P < 0.05）；larger aortic LA，thinner IMT，and smaller PA and LCA were found（all P < 0.05）. The optical density and fluorescence intensity of aortic TGFB2⁃OT1 were lower（all P < 0.05），and the level of serum ICAM⁃1，VCAM⁃1，IL⁃8 and MCP⁃1 was lower（all P < 0.05）. The level of OT1， miRNA4459，LARP1，and SQSTM1 was reduced（all P < 0.05），and the protein expression level of TGFB2⁃OT1， CASP1，and IL1B in the aorta was lower（all P < 0.05）. Conclusion The molecular mechanism of Xueguan Ruanhua Pill in the prevention and treatment of AS is related to the targeted regulation of long ⁃chain non ⁃coding RNA⁃TGFB2⁃OT1，miR4459 and their downstream signals to inhibit the inflammatory response.