Background: Oecophylla smaragdina (red weaver ant) has been traditionally used in ethnomedicine for treating various ailments including diabetes. However, systematic pharmacological evaluation of its antidiabetic potential remains unexplored.

Objective: To evaluate the antidiabetic efficacy of Oecophylla smaragdina methanol extract (MEOS) in alloxan-induced diabetic rats and investigate its pancreatic β-cell protective effects with insights into glycemic control.

Methodology: Adult male Wistar rats were rendered diabetic by single intraperitoneal injection of alloxan monohydrate (120 mg/kg). MEOS was administered orally at 200 mg/kg and 400 mg/kg doses for 28 days. Fasting blood glucose (FBG) was monitored weekly. Oral glucose tolerance test (OGTT) was performed on day 21. Serum lipid profile, renal function tests (creatinine, BUN), hepatic function markers (AST, ALT, ALP), and pancreatic antioxidant parameters (MDA, SOD, CAT, GSH) were assessed on day 28. Pancreatic tissues were subjected to histopathological examination. Acute oral toxicity was evaluated as per OECD 423 guidelines.

Results: MEOS (400 mg/kg) significantly reduced FBG by 58.9% (from 281.0 ± 9.2 to 115.4 ± 5.3 mg/dL) on day 28, comparable to glibenclamide (63.4% reduction). The extract significantly improved glucose tolerance with 44.3% reduction in AUC. MEOS reversed body weight loss and ameliorated diabetic dyslipidemia by reducing total cholesterol (34.5%), triglycerides (37.2%), LDL-cholesterol (51.3%), while increasing HDL-cholesterol (52.2%). MEOS normalized elevated serum creatinine (53.8%), BUN (51.4%), AST (49.7%), ALT (53.0%), and ALP (44.2%). Pancreatic antioxidant analysis revealed significant reduction in MDA (58.2%) with restoration of SOD, CAT, and GSH levels. Histopathological examination confirmed preservation of pancreatic islet architecture, reduced β-cell necrosis, and promoted islet regeneration. No toxicity was observed up to 2000 mg/kg, and the per se group showed no hypoglycemic effect in normal rats.

Conclusion: Oecophylla smaragdina methanol extract demonstrates significant antidiabetic activity through glycemic control, pancreatic β-cell protection, and antioxidant mechanisms, offering a promising, safe, and affordable therapeutic alternative for diabetes management. This study provides the first scientific validation for the traditional use of red ant as an antidiabetic agent.