Background: Type 2 Diabetes Mellitus (T2DM) is a progressive metabolic disorder marked by insulin resistance and chronic hyperglycemia. Although voglibose, an alpha-glucosidase inhibitor, is used in T2DM management, its efficacy is limited, particularly when used alone. This study aimed to investigate whether combining voglibose with ubiquinone and tempol—agents known for their antioxidant, anti-inflammatory, and insulin-sensitizing properties—could enhance therapeutic outcomes. Methods: A total of 62 male Wistar Albino rats were allocated into eight experimental groups, including healthy, diabetic, and various treatment combinations. Glucose metabolism, insulin sensitivity, inflammatory markers, oxidative stress parameters, and the expression levels of GLUT4, IRS1, PIK3R1 genes, as well as histopathological alterations were systematically evaluated for over a 7-week experimental period. Results: The combinations of voglibose + ubiquinone and voglibose + tempol + ubiquinone significantly enhanced insulin secretion, decreased blood glucose and HbA1c levels, and mitigated inflammatory and degenerative tissue alterations, demonstrating superior efficacy compared to voglibose alone and, in some parameters, even to the voglibose + glibenclamide combination. These combinations also restored GLUT4 and PIK3R1 gene expression in muscle tissue. Conclusion: The findings support that supplementing voglibose therapy with ubiquinone and tempol enhances its antidiabetic potential and may serve as a safer and more effective strategy, particularly for patients with advanced or treatment-resistant T2DM. Further clinical research is warranted to confirm translational applicability.