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Several medicinal plants have been used historically and are claimed to be effective in either preventing or treating diabetes. This study aimed to evaluate the effect and the mechanism of O. natrix extract (ONE) as an antihyperglycemic and antihyperlipidemic agents in in vivo experiments. Lipid profile was analyzed using fully automated chemistry analyzer. Blood serum samples were used to measure high-density lipoprotein (HDL), triglycerides (TG), total cholesterol (TC) and Low-density lipoprotein (LDL). The expression levels of AMPK alpha-2 and Glut-4 receptors in diabetic rats were investigated using Western blotting. Oral starch tolerance test (OSTT) and oral glucose tolerance test (OGTT) were determined for the plant extracts at three concentrations on Wistar rats. Acarbose or metformin and glipizide were used as positive controls. Blood glucose levels were measured at −30, 0, 45, 90 and 135 min.ONE (250mg/kg and 125 mg/kg), administered before or after induction of diabetes using streptozotocin (STZ), significantly (p<0.05) reduced the blood glucose level by applying preventive and treatment protocols. The expression levels of Glut-4 receptors were significantly increased in rats given ONE (250 mg and 125 mg/kg) compared to the diabetic rats after 8 days of treatment. ONE (250 mg/kg) enhanced significantly (p<0.05) starch tolerance area under the curve (AUC) and glucose tolerance AUC. O. natrix extracts can activate the Glut-4 receptor, and enhance the glucose and starch tolerance in experimental rats. Hence, this widely distributed species in Jordan can be considered as a potential candidate for management of diabetes. [ABSTRACT FROM AUTHOR]