This study aimed to design the chitosan coated TPGS liposome to enhance the bioavailability of Coenzyme Q10 (CoQ10). Optimization of formulation variables for the preparation of the liposome was performed and then three liposomal formulations (TPGS-liposome, TPGS-chitosome, chitosome) were prepared with narrow size distribution and high encapsulation efficiency. All of three liposomal formulations were stable at pH 1.2 and 7.0 for 24 h without any significant drug leakage. Furthermore, chitosan-coated liposomes showed the strong mucoadhesive properties. All the tested liposomal formulations significantly enhanced the cellular uptake of CoQ10 as compared to the untreated drug. Particularly, TPGS-chitosome appeared to be most effective in improving the cellular uptake of CoQ10 in Caco-2 cells (about 30-folds greater than the untreated powder formulation). In oral pharmacokinetic studies, TPGS-chitosome enhanced the systemic exposure of CoQ10 by 3.4 folds as compared to the untreated powder and also displayed the extended drug release profile for up to 24 h in rats. Compared to the untreated powder CoQ10, TPGS-chitosome significantly improved the antioxidant effect of CoQ10 and reduced the intracellular ROS level. In conclusion, TPGS-chitosome significantly enhanced the oral bioavailability of CoQ10 and prolonged drug release profile in rats, suggesting that TPGS-chitosome could be an effective oral delivery platform to improve the oral bioavailability of poorly absorbable drugs.