Background: The most prevalent liver disease which is rising globally is Non-alcoholic Fatty Liver Disease (NAFLD). Asprosin a newly discovered glucogenic hepatic targeting adipokine has gained great interest. Coenzyme Q 10 (CoQ10) as antioxidant dietary supplement and exercise as an optimal non pharmacological strategy were chosen. Aim: To assess hepato-protective effect of CoQ10 and/or exercise on NAFLD rat model and exploring potential involvement of asprosin/ nuclear factor erythroid 2–related factor 2 (Nrf2) in such effect. Materials and Method: Five groups of rats were conducted for 8 weeks experimental period. Control rats were fed balanced diet. High-fat diet (HFD) group was fed HFD. HFD + exercise group, rats were fed HFD and performed swimming exercise for 60 min/5 days/week. HFD + CoQ10 group, HFD fed rats received CoQ10 20 mg/kg/day/ orally. HFD + CoQ10+ exercise group, rats were fed HFD and performed swimming exercise along with receiving CoQ10. Results: Our findings revealed that HFD led to NAFLD characteristics at both biochemical and histopathological levels. Evident dyslipidemia, insulin resistance, and oxidative stress were documented. These findings were improved by CoQ10 and/or exercise. Asprosin-decline and Nrf2 augmentation were among contributing mechanisms. Conclusion: CoQ10 and/or exercise had a protective effect on a rat model of NAFLD. Asprosin lowering expressions while, enhancing Nrf2 protein expression were among underlying protective impact.