Objective To establish a rat model of chronic kidney disease with hyperhomocysteinemia by high methionine feeding and 5/6 nephrectomy. Then, to evaluate the model by comparing it with the simple high methionine feeding model and simple nephrectomy model. Methods Five-week-old rats were randomly divided into four groups: sham, high methionine (feeding on a high methionine diet), nephrectomy (5/6 nephrectomy), and compound model (high methionine diet and 5/6 nephrectomy) groups. Arterial blood pressure, echocardiography, and serum biochemical indices were measured. Changes in the tension of isolated thoracic aortic vascular rings were observed and expression of pp85, p-Akt, and p-eNOS (Ser1177) proteins was detected. HE staining was used to observe pathological changes in renal, myocardial, and aortic tissue. Results Compared with the sham group, arterial blood pressure of the three model groups increased continuously (P<0.01). Arterial blood pressure of compound model group was significantly higher than high methionine group and nephreetomy group(P<0.05). Compared with the sham group, echocardiography indexes LVEDd, LVEDV, LVESV, and SV of the three model groups were significantly different (P<0.05). Compared with the sham group, serum homocysteine and methionine in high methionine and compound model groups were increased (P<0. 01), while, creatinine, urea nitrogen, total cholesterol, and high-density lipoprotein in serum were increased significantly (P<0. 05) and triglyceride was significantly decreased (P<0. 05) in nephrectomy and compound model groups. Compared with the sham group, vascular ring relaxation curves of model groups induced by vasodilators shifted to the right, and the Emax and EC50 of the relaxation effect induced by acetylcholine and sodium nitroprusside in the compound model group were significantly different from those in the simple model group (P<0. 05). Compared with the sham group, expression of p-Akt and p-eNOS in aortic tissue of the compound model group was statistically significant (P<0. 05). Pathological changes were observed in renal, myocardial, and aortic tissues of the model animals, among which the compound model group had more severe pathological changes. Conclusions A rat model of chronic kidney disease with hyperhomocysteinemia can be established by combining a high methionine diet and 5/6 nephrectomy. Compared with the simple models, the functional and morphological changes are significantly different in the compound model, which can be applied to fundamental research on chronic kidney disease with hyperhomocysteinemia.