. This study was designed to evaluate the protective role of Neohesperidin (NH) on streptozotocin (STZ)-induced diabetes mellitus in rats and determine the associated mechanisms. Rats were randomized into six groups: Normal control, STZ (60 mg/kg) induced diabetic rats, STZ + NH (200 mg/kg), STZ + NH (200 mg/ kg), STZ + Glibenclamide (600 mu g/kg) and NH alone (200 mg/kg). After 45 days, the plasma glucose, HbAC1, insulin level, carbohydrate metabolizing enzyme (Glucokinase, Glucose 6-Phosphatase, Fructose 1,6 -bisphos-phatase and Glucose 6-phosphate dehydrogenase), biochemical parameters such as AST, ALT, urea, uric acid, creatinine, total cholesterol, triglycerides, phospholipids, Free fatty acids, Low-density Lipoprotein-C and High-density Lipoprotein-C and antioxidant enzymes status were measured. A pathological condition of the liver, kidney and pancreas was examined by hematoxylin-eosin (H&E) staining. After 45 days of treatment, the results showed that NH had significant anti-hyperglycemic and total cholesterol-lowering effects and its treatments improved serum high-density lipoprotein (HDL) cholesterol levels. NH also enhanced glucose tol-erance and the histological state of the liver in diabetic rats and exhibited intriguing antioxidant activities.