Oxidative stress plays a crucial role in tissue damage occurring in diabetes mellitus (DM). A number of studies reported that antioxidants can attenuate the complications of DM. The present study was undertaken to study the histopathological and biochemical effects of oxidative stress on hepatic and renal tissue in streptozotocin-induced DM in rats, and to evaluate the role of enalapril and nicorandil and their combination in combating oxidative stress-induced pathological effects. Diabetic rats were divided into groups of six rats and received 10mg/kg, intraperitoneally of enalapril (an angiotensin-converting enzyme (ACE) inhibitor that is used in the treatment of hypertension), 0.1mg/kg, orally of nicorandil (a potassium channel opener which is efficacious in the treatment of hypertension and angina pectoris) and their combination once daily for one month. Analysis of plasma and tissue parameters of oxidative stress was done. In addition, specimens were taken from the liuver and kidney for histopathological examination. Plasma of diabetic rats showed significant elevation of glucose level and alteration in oxidative stress parameters. Cytochemical studies on hepatic and renal tissues showed altered levels of oxidative stress parameters. Histopathological examination of hepatic and renal specimens showed degenerative changes. Treatments of the diabetic rats with enalapril, nicorandil and their combination led to improvement of the abnormalities in oxidative stress parameters and also in the histopathological abnormalities of the liver and kidney. These results indicate that oxidative stress occurring in DM leads to structural damage in many organs, even in early stages of the disease. The antioxidant activities of enalapril, nicorandil and their combination may play an important role in protection against oxidative stress in DM.