Objective The purpose of this study was to explore the effects of Composition of Ophiopogon polysaccharide， Notoginseng total saponins and Rhizoma Coptidis alkaloids（CONR） on proliferation of diabetic atherosclerotic rabbit modle by interventing TGF-β1/p38MAPK/CREB signal pathway using Serum pharmacology. Methods 1. Select 5 pure male New Zealand rabbits， and 4 of them were respectively given CONR 450 mg/kg， CONR 150 mg/kg each day； Simvastatin 3 mg/kg for 10 days； SB203580 2 mg/kg abdominal injection， 12 h repeated for 10 days； the other one was given 20mL saline solution daily. Preparation of drug containing serum； Another daily saline solution was 20 mL of saline. Drug containing serum was prepared. 2. Normal male New Zealand white rabbit were intravenous injected alloxan and feed high-fat diet ， then abdominal aortic balloon injury was done to induce diabetic atherosclerosis model. 3. The rabbit’ aorta abdominalis SMC was isolated and cultured， and the third generations of cells were used for the experiment. 4. Grouping： set up the normal group， model group， CONR high dose group， the CONR low-dose group， SB203580 group， simvastatin group， and the experimental group were given drug-containing serum， the blank group， model group normal serum. 5. CCK 8 method is used to determine the corresponding absorbance， and we calculate 50% inhibition concentration； Western blotting was used to detect the expression of TGF-β1、 p-p38MAPK、 p-CREB protein of diabetic arteriosclerosis rabbits. Results The experimental results showed that CONR had inhibitory effect on the proliferation of smooth muscle cells， and the concentration of 50% inhibition rate（IC50） was 12.53 g/mL. Simvastatin group， SB203580 group and CONR high， low dose group had inhibitory effect on TGF-β1、 p-p38MAPK、 p-CREB protein expression， which was statistically significant compared with the model group（P<0.01）. The inhibitory effect of CONR high， low dose group and simvastatin group on p-p38MAPK protein was better than that of SB203580 group（P<0.01） ， and there was no statistically significant difference between the three groups（P<0.01）. Simvastatin group， SB203580 group and CONR high， low dose group had inhibitory effects on TGF-β1、 p-CREB， and there was no statistically significant difference between the four groups（P>0.05）. Conclusion Composition of Ophiopogon polysaccharide， Notoginseng total saponins and Rhizoma Coptidis alkaloids（CONR） may be able to inhibite proliferation of diabetic atherosclerotic rabbit modle by interventing TGF- β1/p38MAPK/CREB signal pathway using Serum pharmacology.