This study was conducted to prepare chitosan nanoparticles (CNPs), to determine their properties and to evaluate the synergistic protective role of CNPs alone or in combination with quercetin (Q) against oxidative stress and hepatotoxicity in rats. Female Sprague-Dawley rats were divided into 12 groups (7 rats/group) and were maintained on their respective diet for 3 weeks as follow: control group, the group treated with CCl4 (100 mg/kg b.w twice a week); the groups received CNPs at low and high doses (140 and 280 mg/kg b.w); the group received Q (50 mg/kg b.w); the groups received CNPs at the low or high doses plus Q and the groups treated with CCl4 plus Q and/or CNPs at the two tested doses. Blood and liver samples were collected at the end of experiment period for biochemical and histological studies. The results indicated that chitosan showed deacetylation degree of 17.5% and 19.2% and the molar mass average of monomer was 168.35 g/mol and 169.1 g/mol by UV and IR methods respectively. The particle size of CNPs was around 100 nm with a rough surface. The in vivo results revealed that CCl4 induced biochemical and histological changes typical to those reported in the literature. Animals treated with CNPs at the two tested doses alone or in combination with Q were comparable to the control. CNPs alone or plus Q succeeded to induce significant improvements in the biochemical parameters and histological picture of the liver in rats treated with CCl4. This improvement was in dose-dependent manner for CNPs and was * Corresponding author. E. S. El-Denshary et al. 37more pronounced in the group treated with the high dose plus Q. It could be concluded that both CNPs and Q could induce protection against hepatotoxicity. Consequently, CNPs was a promise candidate as drug delivery in liver diseases treatments.