Capsaicin (CAP) and alpha-tocopherol (TOC) have antioxidant properties. We investigated effects of CAP and TOC on mitochondrial oxidative stress and mitochondrial bioenergetics in liver of mice fed HFD. AST, ALT, glucose, homeostasis model assessment-insulin resistance index ((HOMA-IR)) and mitochondrial oxidative stress parameters increased, whereas oxidative phosphorylation (OXPHOS) enzymes, tricarboxylic acid cycle (TCA) enzymes, ATP level and mitochondrial metabolic function (MTT) decreased in mice fed a HFD compared to the fed a standard diet (NC). Treatment of HFD together with CAP (HFC group), TOC (HFT group) or TOC and CAP (HCT group) can ameliorate the examined parameters. Because co-treatment with CAP and TOC displayed a better ameliorating effect on liver redox status and mitochondrial bioenergetics functions, they can be useful to protect against HFD and oxidative stress-related in liver diseases.