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Epidemiological outburst of type 2 diabetes is of great global concern. T2D starts with Insulin Resistance (IR) which arises largely due to environmental factors and to a lesser extent due to genetic factor. IR gradually develops into T2D and encompasses a wide array of conditions including Impaired Glucose Tolerance (IGT), hyperinsulinemia, Impaired Fasting Glucose (IFG), and Impaired Insulin Release (IIR). Initiation of IR increases the risk of Cardiovascular Diseases (CVD). Therefore, early diagnosis and management of IR and its related outcomes (hyperinsulinemia, hyperglycemia, and dyslipidemia) should be the prime focus of intervention therapies. Present research aimed to evaluate the synergistic combination of Magnesium orotate (MOD), Menaquinone- 7 (MK-7), and Cholecalciferol (CHOL) for the management of these therapeutic targets in the Streptozotocin–Nicotinamide-induced T2D Wistar rat model. Synergistic combination was found to be superior over its individual components in management of hyperglycemia, impaired insulin secretion, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and dyslipidemia ( p < 0.01 or p < 0.05). Its effect was found to be equivalent or better than reference drugs ( p < 0.01 or p < 0.05). Histopathological analysis depicted that combination treatment was able to regenerate and preserve pancreatic β-cell mass in diabetic rats. In conclusion, combination studied in present research can be evaluated further under clinical settings for management of IR and its related outcomes.