Diabetes mellitus is a chronic metabolic condition clinically characterized by hyperglycemia, with excessive production of free radicals and the formation of advanced glycation end products playing major roles in the pathogenesis and progression of this disease. Antioxidants, increasingly recognized for their ability to minimize damage caused by diabetes-related oxidation, have been gathering attention. This study aimed to use Urtica dioica extract, combined with vitamin E, to investigate its possible beneficial synergy on fasting blood glucose (FBG), antioxidant levels, and histological changes in diabetic rats. By applying three phytochemical methods, we obtained Urtica dioica extract and tested its toxic effects to ensure its safety. Male albino rats were induced with diabetes and divided into six groups: one experimental group, and groups receiving metformin, vitamin E, Urtica, a vitamin E-Urtica combination, and a control. The potential usage of this treatment for managing type-2 diabetes was established. Serum and non-fasting blood (NFB) glucose levels were captured at each follow-up. MDA concentration in adipose tissue and total antioxidant activity in mouse serum were assessed in vitro and in vivo experiments. Additionally, histomorphological analysis of the pancreatic tissues was conducted. The combination therapy of Urtica dioica and vitamin E provided greater benefits in body weight, FBG levels, and antioxidant activity than individual treatments. The combination group showed positive changes, including increased body weight, lowered levels of FBG, and higher antioxidant activity, as evidenced by decreased levels of MDA and increased total antioxidant status (TAOS) in pancreatic tissue and serum. The association of Urtica dioica extract and vitamin E should not be underestimated in treating hyperglycemia and oxidative stress complications of diabetes, making this combination a promising supplementary therapy for hyperglycemia and oxidative stress.