Oxidative stress is a phenomenon caused by an imbalance between the production and accumulation of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. Oxidative stress has been suggested to be a contributory factor in the development and complication of diabetes. In the present study, the effect of tetrahydrocurcumin (THC), one of the active metabolites of curcumin, on the antioxidant status of streptozotocin-nicotinamide-induced diabetic rats was investigated. The effect of THC compared to pterostilbene on the occurrence of oxidative stress in the brain of rats during diabetes was also investigated by measuring the extent of oxidative damage as well as the status of the antioxidant defense system. Oral administration of THC at 80 mg/kg and pterostilbene at 40 mg/kg body weight of diabetic rats for 45 days resulted in significant reduction in blood glucose and significant increase in plasma insulin levels. Oxidative stress results from an imbalance between the generation of oxygen-derived radicals and the organism’s antioxidant potential. Thiobarbituric acid reactive substances (TBARS) and hydroperoxides from brain of diabetic rats were found to significantly increase and enzymatic antioxidants, namely superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) and non-enzymatic antioxidants, namely vitamin C, vitamin E and reduced glutathione (GSH) were found to significantly decrease in diabetic control rats. Administration of THC and pterostilbene significantly decreased the levels of TBARS and hydroperoxides accompanied with a significant increase in the activities of enzymatic antioxidants as well as non-enzymatic antioxidants. The anti-diabetic and antioxidant effects of THC are more potent than those of pterostilbene.