This study was designed to investigate the anti-diabetic effect of cucurbitacin extracts from Citrullus colocynthis in Streptozotocin-Nicotonamide (STZ-NIC) induced diabetes in rats. The diabetes was induced by single dose of STZ (65 mg/kg) in citrate buffer after 15 min of I/P injection of nicotinamide (110 mg/kg) in normal saline. After seven days of induction of diabetes, the diabetic animals were treated for further eight weeks with (100mg/kg) cucurbitacin extracts or (100mg/kg) metformin or combination of both. Blood glucose estimation was performed every week of the study. STZ-induced diabetic rats showed marked hyperglycemia all over the study period. The expression levels of GSI, insulin, GK and G6PDH were reduced. The glycated haemoglobin, ALT, AST and creatinine levels were significantly increased while the level of liver glycogen was decreased in diabetic rats. Supplementation with (100 mg/kg) cucurbitacin extracts for eight weeks significantly ameliorated the alterations in fasting blood glucose, liver glycogen, glycated haemoglobin, creatinine, ALT, AST and the expression levels of GSI, insulin, GK and G6PDH in diabetic rats. Thus, the present study suggested the potential of citrullus colocynthextract in diabetes as well as related complications.