Objective: To investigate the mechanism of atherosclerotic vulnerable plaque formation based on the regulation of connective tissue growth factor (CTGF) expression by animal model analysis. Methods: The atherosclerosis model were established in 8-10 weeks old female littermate CTGF^+/+ApoE^−/− mice (the observation group) and CTGF^−/−ApoE^−/− mice (the control group). The rats were fed with high-fat and high-cholesterol diet, the state of the mice was observed, the blood lipid index was measured, and the pathological condition of the vulnerable plaques were recorded. Results: All mice were successfully completed there were no local or systemic adverse reactions were observed. The TC, TG and LDL-C values of the observation group were higher than those of the control group at 2 and 4 weeks after model establishment, and the HDL-C value were lower than that of the control group, compared the difference were statistically significant (P<0.05). The atherosclerotic plaques were formed in the arteries of the two groups at 2 and 4 weeks after modeling, the atherosclerotic plaques in the heart and aortic roots of the observation group were more significant than the control group, and the lipid core area were increased and the foam cells were increased significantly. The area of vulnerable plaques in the observation group at 2 and 4 weeks after modeling were significantly higher than that in the control group (P<0.05). The relative expression level of MMP-9 in the observation group were higher than that in the control group, and compared the difference were statistically significant (P<0.05). Conclusion: The lack of expression of CTGF signaling pathway can inhibit the expression of MMP-9 and promote the normal metabolism of blood lipids, thus inhibit the occurrence of atherosclerotic vulnerable plaque.