Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients. To prevent the development of this disease and to improve advanced kidney injury, effective therapies directed toward the key molecular target are required. Proanthocyanidin (PA) and thymoquinone (TQ) have been reported to be effective in treating DN, while little is known about their mechanism of action and their combination. Aim: This study was designed to investigate the possible beneficial effects of (TQ), (PA) and their combination to attenuate DN in rats. Materials and Methods: Rats were divided into five groups: group 1 (control), group 2 (diabetic untreated), group 3 (diabetic treated with PA), group 4 (diabetic treated with TQ) and group 5 (diabetic treated with PA+TQ). Diabetes was induced in groups 2-5 by a single dose of 65 mg/kg streptozotocin (STZ) in citrate buffer pH 4.5. Two days after STZ treatment, development of diabetes in the experimental groups was confirmed by measuring blood glucose. Rats in group 3 were given PA (250 mg/kg), rats in group 4 were given TQ (50 mg/kg) and rats in group 5 were given PA+TQ (250+50 mg/kg respectively) once a day orally for 12 weeks starting 2 days after STZ injection. Results: In this work, novel data correlate the relation between reactive oxygen species; advanced glycation end products; IL-6 and DN were obtained. Treatment of rats in groups 3-5 with PA, TQ and PA+TQ was significantly increased- the reduced body weight, the reduced glutathione concentration and activity of superoxide dismutase. The elevated levels of urea, creatinine, nitric oxide, malondialdehyde and IL-6 in group 2 were significantly reduced as a result of the treatment. Conclusion: These findings suggest that PA and TQ treatment exerts a therapeutic protective effect in diabetes by decreasing oxidative stress and attenuating DN. Consequently, TQ and PA may be clinically useful for protecting diabetic kidney against oxidative stress.