Background and purpose: Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by β-cell dysfunction, insulin resistance, and elevated blood sugar levels. Several studies have explored the therapeutic potential of Coenzyme Q10 (CoQ10) in managing diabetes, but no reports have examined the possible mechanism of CoQ10 in T2DM. Here, we report that CoQ10 protects pancreatic β-cell structure and function possibly by modulating the expression of mir-33a/ mir-21/SREBP1 and we describe the more detailed tissue alterations. Experimental approach: The study was made by randomly dividing of rats into three groups (n = 10); control, diabetic, and diabetic + CoQ10. The diabetic + CoQ10 group were diabetic rats that concurrently administered CoQ10 (20 mg/kg/i.p.) 3 d/wk for eight weeks. In addition to microscopic examination, the study involved evaluating of glucose, insulinand oxidative profile in the serum along with analyzing the levels of cholesterol, mir-33a, mir-21 and SREBP1 in pancreatic tissue. Findings/Results: Our results revealed that CoQ10 restores glucose/insulin homeostasis, oxidative parameters, cholesterol levels and the expressions of mir-33a, mir-21 and SREBP1 (p≤ 0.05). In addition, the CoQ10-treated diabetic rats showed increased active β-cells compared to the diabetic group. The immuno-histochemical examination of insulin revealed a higher quantity and larger size of pancreatic islets in the experimental group. Conclusion and implications: The restoration of -cell integrity following treatment with CoQ10 may elucidate the therapeutic benefits of this compound in diabetes management, potentially through its influence on the pancreatic expression of mir-33a/mir-21/SREBP1, subsequently maintaining healthy tissue.