Background: Diabetes mellitus (DM) affects the musculoskeletal system through itsmetabolic perturbations. Exercise modulates blood sugar levels and increases the bodys sensitivityto insulin in patients with DM. Objective: This study aimed to investigate the potential effects of combined quercetin and coenzymeQ10 (CoQ10) supplements with or without exercise on the histological, biochemical andmolecular structures of diabetic rats skeletal muscle Methods: A total of 64 adult male albino rats were divided into six groups: control, trained nondiabetic,non-trained diabetic, diabetic rats treated with combined CoQ10 and quercetin, diabetic ratswith treadmill training, and diabetic rats treated with treadmill training and CoQ10 and quercetin.Blood and skeletal muscle samples were obtained from all groups for routine histological examinationand biochemical determination of cytokine levels and protein activities. Quantitative real-timepolymerase chain reaction (qRT-PCR) and morphometric analysis of PAS and Bax expressionswere also performed. Results: Biochemical analysis revealed improvement in all studied parameters with combined Co-Q10 and quercetin than exercise training alone. Combined treatment and exercise showed significantimprovement in all parameters especially interleukin 6 and malondialdehyde. Fibronectin typeIII domain-containing protein 5 (FNDC5) expression and irisin levels increased in all trainedgroups but combined treatment with exercise significantly increased their levels than exercisealone. Histological analysis revealed improvement after exercise or combined treatment; however,when exercise was combined with CoQ10 and quercetin, marked improvement was observed. Conclusion: the combination of CoQ10 and quercetin could be promising in preserving musculoskeletalfunction in patients with DM concomitantly with physical exercise.