The aim of the present study was to evaluate the possible roles of hyperforin against hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). Biochemical parameters were measured following hyperforin treatment (10 mg/kg, i.p.) for 7 days. Hyperforin treatment significantly reversed the elevations in plasma glucose, triglycerides, total cholesterol and LDL-cholesterol. Hyperforin also reversed the declines in plasma HDL-cholesterol and liver glycogen, but did not reverse the change in plasma insulin levels when compared to the diabetic control rats. Hyperforin treatment also reversed the oxidative stress induced by streptozotocin. Moreover, the effect of the hyperforin on peripheral glucose utilization in normal rats was evaluated by an oral glucose tolerance test (OGTT). Hyperforin treatment significantly increased (p < 0.05) the glucose tolerance compared to the vehicle in OGTT. The antihyperglycemic, antihyperlipidemic and antioxidant activities of hyperforin (10 mg/kg, i.p.) were comparable qualitatively to glibenclamide (1 mg/kg, p.o.). In conclusion, we report for the first time through an in vivo study that hyperforin is potentially valuable for the treatment of diabetes and its associated hyperlipidemia and oxidative stress by enhancing the glucose utilization by peripheral tissues such as muscle and adipose tissues.