[Purpose] The present study was aimed to develop quercetin (QUE)-loaded poly(lipoic acid) nanoparticles (pLA/QUE) to improve chemical stability in the gastrointestinal (GI) tract, oral bioavailability (BA), and hepatoprotective properties of QUE.[Methods] pLA/QUE was prepared by emulsion solvent evaporation technique with ultrasonication, followed by freeze-drying, and its physicochemical properties were evaluated in terms of particle size distribution, morphology, chemical stability, and release characteristics. The pharmacokinetic behavior of QUE and hepatoprotective effects were assessed in a rat model of hepatic injury after oral administration of QUE samples.[Results] The mean particle size of pLA/QUE was 185 nm with a high encapsulation efficiency of QUE, as evidenced by 84.8%. Sustained release of QUE was observed in pLA/QUE compared with crystalline QUE, and significantly enhanced QUE stability even under physiological pH in the GI tract. Orally-dosed pLA/QUE (50 mg QUE/kg) in rats exhibited significantly prolonged systematic exposure with increases in mean residence time of 3-fold higher than that of crystalline QUE. The oral BA of QUE in pLA/QUE and crystalline QUE groups was calculated to be 29 and 0.19%, respectively, suggesting significant enhancement of oral absorbability, possibly due to the improved stability and dissolution property of QUE in the GI tract. In hepatic injury model rats, pLA/QUE (50 mg-QUE/kg, p.o.) led to marked reductions in the plasma biomarker levels of alanine aminotransferase and aspartate aminotransferase by 70 and 46%, respectively, compared with the vehicle group. pLA/QUE also exhibited improved antioxidant effects as evidenced by the enhanced activities of hepatic glutathione, superoxide dismutase, and a decrease in the level of malondialdehyde, a marker of lipid peroxidation.[Conclusion] The strategic application of pLA system to QUE might be a promising option to improve the nutraceutical properties of QUE.