Annona muricata, an herbal plant commonly used in traditional medicine to manage numerous diseases, diabetes as other diseases could be managed with herbal medicine. This study was designed to be investigated the antidiabetic, hypolipidemic, renal protective, and antioxidant effects of aqueous extracts of Annona muricata as used alone or combined with metformin in streptozotocin (STZ)-induced diabetic rats. Methods: the study was involved twenty adult Wister albino rats in four groups (five rats in each) and designated as groups, control group (1), and experimental groups (2, 3, 4). Diabetes was induced in experimental groups by 60 mg/kg intravenous streptozotocin injection. Group 2: serves as a diabetic control group, Group 3: diabetic rats treated with oral administration of 100 mg/kg of Annona muricata aqueous extract, Group 4: diabetic rats treated with combination (100 mg/kg aqueous extract of Annona muricata + 50 mg/kg metformin). The treatment continuous daily for 4 weeks to determine the levels of blood glucose and biochemical analysis. Result: aqueous extract of Annona muricata was reduced the serum glucose level effectively in streptozotocin-induced diabetic rats, by 48% and 55% after 28 consecutive days of treatment when used alone and with metformin, respectively. These compared to the preliminary values and the reduction was statistically significant compared to a diabetic control group. Daily oral administration of 100 mg/kg aqueous extract of Annona muricata for 4 weeks to streptozotocin-induced diabetic rats significantly reduced the level of total cholesterol, urea, creatinine, and MDA, whereas the reduction was non-significant in triglyceride and VLDL-cholesterol levels as compared to the non-treated diabetic group. However, the reduction is more significant in streptozotocin-induced diabetes rats that were treated with a combination of Annona muricata and metformin when compared to the diabetic control group. Conclusion: Aqueous extracts of Annona muricata have anti-diabetic action through their hypoglycemic, hypolipidemic, renal protective, and antioxidant effects in streptozotocin-induced diabetic rats. Thus, can be used alone or with anti-hyperglycemic drugs as metformin in the management of DM. The combination is preferred in severe hyperglycemic cases with more hypoglycemic effect requirements.