BACKGROUND Uncontrolled diabetes mellitus causes neuronal damage because of increased intracellular glucose. Natural products as complementary therapy may reduce neuronal complications. This study investigated whether fish oil (FO) and wheat germ oil (WGO) supplementation protects the brain in streptozotocin (STZ)-induced diabetic rats by estimating lipid peroxidation and the inflammatory and anti-oxidant status of the brain. METHODS Diabetes was induced in male Wistar rats by a single i.p. injection of STZ (60 mg/kg). Four weeks after diabetes induction, rats were divided into an untreated group and a group supplemented with 0.4 g/kg per day FO +WGO mix, p.o., for 4 weeks. Brain oxidant status was assessed by measuring nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH), the GSH/oxidized glutathione (GSSG) ratio, and superoxide dismutase (SOD) and catalase (CAT) activity. Inflammatory biomarkers (tumor necrosis factor [TNF]-α levels and nuclear factor (NF)-κβ immunoreaction) were measured in brains, combined with histological studies. Cholinergic function was assessed on the basis of acetylcholine (ACh) levels and acetylcholinesterase (AChE) activity. RESULTS Supplementation with FO + WGO reduced MDA and NO ( P  < 0.001) in diabetic rat brains and enhanced brain antioxidant capacity, as evidenced by increased GSH, GSH/GSSG ratio ( P  < 0.01), and SOD and CAT activity ( P  < 0.01). In addition, FO + WGO supplementation suppressed NF-κB immunoreaction and TNF-α levels ( P  < 0.001). Cholinergic function was improved by FO + WGO as a result of increased ACh levels and reduced AChE activity ( P  < 0.001). CONCLUSIONS Supplementation of the diet with the FO + WGO mix modulated diabetic brain injury and this mix could potentially be used for preventing diabetic neurodegenerative sequelae.