Diabetic encephalopathy is characterized by impaired cognitive functions that involve neuronal damage triggered by glucose driven oxidative stress. The objective of the present study was to determine whether N-acetylcysteine (NAC) supplementation ameliorates learning and memory deficits caused by hyperglycemia-induced oxidative stress in experimental diabetes. Male Wistar rats (200-250 g) were rendered diabetic by a single intraperitoneal injection of streptozotocin (50 mg/kg). Cognitive deficits were observed in diabetic animals assessed using elevated plus maze test after 8 weeks of induction of diabetes. Acetylcholinesterase activity, a marker of cholinergic function, was decreased by 15.6% in the cerebral cortex, 20.9% in cerebellum and 14.9% in brain stem of diabetic rats compared to control rats. There was an increase in lipid peroxidation in cerebral cortex (21.97%), cerebellum (20.4%) and brain stem (25.5%) of diabetic rats. This was accompanied by decrease in glutathione and total thiol content along with decrease in the activities of superoxide dismutase, catalase and glutathione reductase. However, glutathione peroxidase activity increased by 11.2%, 13.6% and 23.1% in cerebral cortex, cerebellum and brain stem respectively, while the activity of glutathione-s-transferase decreased only in cerebral cortex (21.7%). Supplementation with NAC (1.4 g/kg/day in drinking water) significantly attenuated cognitive deficits and oxidative stress in diabetic rats. Our results emphasize the involvement of increased oxidative stress in cognitive impairment in diabetic animals and point towards the potential beneficial role of NAC as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and treatment of diabetic encephalopathy.