In the present study, the biochemical effect of nanocurcumin (nanoCUR) compared with Gliclazide (GLZ) on the diabetic rats was studied. Forty male albino rats (Sprague Dawley) weighted 110 ± 20 g were used. Rats were randomly separated into two groups. Control, received no treatment. Streptozotocin (STZ)-induced diabetic groups take 5 ml/kg of STZ in normal saline daily for 30 days, further divided into diabetic non-treated group, did not receive any treatment: diabetic group treated by nanoCUR, received 15 mg/kg/day of nanoCUR orally for 30 days; diabetic group treated by GLZ, received 2 mg/kg/day of GLZ for 30 days. The mean body weights of all rats were registered and serum samples were collected for determination of fasting blood glucose (FBG), insulin concentration, liver glucokinase (GK), and glycogen synthase (GS) activities. Liver tissues were collected for determination of mRNA expression of insulin (INS), insulin receptor A (IRA), glucokinase (GK), and glucose transporter 2 (GLUT2). The results revealed a significant reduction of body weight in diabetic rats, with no significant differences in nanoCUR and GLZ groups. There was a decline in FBG levels and significant elevation of INS levels, GK, and GS activities in diabetic rats received nanoCUR and GLZ. mRNA expression of INS, IRA, GK, and GLUT2 significantly upregulated in diabetic rats received nanoCUR and GLZ. The amazing observation was a non-significant difference in all measured parameters between nanoCUR and GLZ groups. In conclusion, nanoCUR is able to improve cellular uptake of glucose, the hepatic insulin signaling, and insulin sensitivity in diabetic rats. Its effect was similar to standard hypoglycemic drug (GLZ).