Evidences demonstrated that the effect on anti-proteinuria and renal protection of Chinese herbs combination with ACEi or ARB seemed to be better than ACEi or ARB alone. Astragaloside IV could decrease the urinary albumin excretion rate and could protect against renal injuries linking to its anti-oxidation ability. We aimed to investigate the effect of astragaloside IV combined with ACEi on diabetic nephropathy and to explore whether its underlying mechanism is dependent on anti-oxidation. 8-week-old male experiment mice were randomly assigned to five groups: lean wild type (wt) group, db/db group, db/db + astragaloside IV group, db/db + enalapril group, db/db + combination therapy with astragaloside IV and enalapril group. During the experiment, 24 hours urinary albumin, fasting glucose, body weight, and metabolic parameters were monitored in regular intervals. At the end of the study, tail blood pressure, serum H2O2, lipid, and liver function were measured and kidney histological injuries were evaluated. Results of the study indicated that combination therapy with astragaloside IV and ACEi further reduced 24 hours urinary albumin excretion rate, blood pressure, and body weight. Combination therapy reduced the foot process width, glomerular base membrane thickness, glomerular tuft cell proliferation, tubular cell atrophy, tubular base membrane thickness, and improved tubular cell proliferation. It modulated the body H2O2 metabolism and up-regulated the expression of the catalase in renal cortex. Astragaloside IV combined with ACEi exerted renal protective effects in db/db mice more significantly than their individual used. The mechanism possibly involved their synergistic effects on anti-oxidation. IJCEP Copyright © 2020.