The use of nanoparticles in medicine is an attractive proposition. In the present study, evaluation of the anti-diabetic activity of zinc oxide nanoparticles (ZnONPs) on insulin, insulin receptors and insulin receptors substrates gene expression in streptozotocin-induced diabetic rats were investigated. One hundred and sixty male albino rats with weight 130 ± 30 and age 12-16 weeks were used. Animals were grouped as follows: control; did not receive any type of treatment , control positive received single daily oral dose of 5 mg/kg ZnONPs in suspension, diabetic rats; received a single intra peritoneal dose of streptozotocin (50 mg/kg), diabetic + insulin; received a single daily subcutaneous dose of insulin (2U/kg) , diabetic + ZnONPs I, received single daily oral dose of 5mg/kg ZnONPs in suspension, diabetic + ZnONPs II, received single daily oral dose of 10mg/kg ZnONPs in suspension , diabetic+ ZnONPs + insulin I; received single daily oral dose of 5mg/kg ZnONPs in suspension and a single daily subcutaneous dose of insulin (2U/kg) and diabetic+ ZnONPs + insulin II; received single daily oral dose of 10mg/kg ZnONPs in suspension and a single daily subcutaneous dose of insulin (2U/kg) . The pancreatic insulin gene expression, hepatic insulin receptor A (IR-A), hepatic insulin receptor substrate-2 (IRS-2) and muscular insulin receptor substrate-1 (IRS-1) mRNA levels were determined. The results indicated that the expression of insulin, IR-A, IRS-1 and IRS-2 were depressed in diabetic rats, while they are induced in rats that administrated ZnONPs and/or insulin in a dose dependant. In conclusion, zinc oxide nanoparticles act as potent inducer for insulin, insulin receptors and insulin substrates gene expression.