Background. Diabetes mellitus is a metabolic disorder characterized by hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism, resulting from defects in insulin secretion, insulin action, or both. Managing diabetes mellitus with currently available drugs is costly, and the chances of side effects are high, leading to further studies for new and better medications from plant sources with the affordable and lower side effects. This study aimed to evaluate the antioxidant, antihyperglycemic and, antihyperlipidemic effects of the 80% methanolic extract of Datura stramonium leaves in Streptozotocin-induced diabetic mice. Methods. Male Swiss albino mice were induced into diabetes using 150mg/kg of STZ. The FBG measurements were done on 0, 7th, and 14th days of treatment. At the end of the experiment, on the 14th day mice were anesthetized with diethyl ether. Then, blood was drawn by cardiac puncture to assess TC, TG, LDL-C, and HDL-C. The antioxidant activity of the extract was determined using a DPPH assay. The data were entered into Epi-Data version 4.6, exported to SPSS version 26.0, and analyzed using a one-way ANOVA followed by a Tukey post hoc test. P < 0.05 was considered statistically significant. Result. D.stramonium leaves extract showed significant blood-glucose-lowering activity. The extract of D.stramonium reduced the fasting blood glucose level by 19.71%, 30.27%, 40.95%, and 45.67%, respectively, for D. stramonium 100, 200, 400, and GLC 5 mg/kg on the 14th day of treatment. Diabetic mice treated with D.stramonium for 14 days showed a significant decrease in serum TC, LDL, and serum TG and a significant increase in body weight, and HDL level as compared to diabetic negative control. Antioxidant activities of the leaves extract were comparable to ascorbic acid with an IC50 of 172.79 µg/ml. Conclusion. This study showed that D. stramonium leaves extract possesses significant anti-hyperglycemic, antihyperlipidemic and antioxidant activities.