Background: Diabetes is a metabolic disease prevalent worldwide in all age group of people. The source of diabetes is due to an oxidation process that can produce free radicals. An increase in oxidative free radicals in the body is reported to be one of the several causes of diabetes. The best remedy to combat oxidative stress is the use of antioxidants, which inhibit and scavenge free radicals. Aim: This study has been undertaken to evaluate the antioxidant activity and antidiabetic effect of mulberry leaf extract in diabetic mice. Materials and Methods: Antioxidant activity of mulberry leaves was determined by 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assay. Antidiabetic assay of mulberry leaf extract was analyzed by oral administration of leaf extract up to 3 weeks in diabetic mice induced by streptozotocin. Results: In vitro antioxidant activity in both DPPH and FRAP assays showed significantly (P < 0.05) higher inhibition of free radicals than that with ascorbic acid. Diabetic mice fed with mulberry leaf extract showed increment (+25.88%) in body weight and a significant reduction in blood glucose concentration (−71.58%). Further, glucose-6-phosphate dehydrogenase enzyme activity was significantly (P < 0.05) increased, whereas activities of other enzymes particularly catalase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase were decreased in diabetic mice after oral administration of mulberry leaf extracts. Histology of liver revealed regeneration of hepatocytes, central vein, and nucleus. Conclusion: This study demonstrated that S-1708 mulberry variety has a potential therapeutic value in diabetes and related complications.