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In this study, hepatoprotective effect of chitosan nanoparticles (CHNPs) was studied against alcohol and fatty diet induced oxidative stress and liver injury in rats. Sixty rats were randomly divided into six groups and received basal diet and normal drinking water (group I and II), basal diet and 10% (v/v) ethyl alcohol (group III and IV) or Fatty diet (30% Wt/Wt fat content) (group V and VI). The groups II, IV and VI were received one daily oral dose (450 mg/kg) of chitosan nanoparticles. The in vivo results revealed that alcohol and fatty diet-induced biochemical changes typical to those reported in the literature. Animals treated with CHNPs were comparable to the control. CHNPs succeeded to induce significant (p < 0.05) improvements in all biochemical parameters of the liver. It could be concluded that CHNPs could induce protection against hepatotoxicity. Consequently, CHNPs was a promising candidate as a drug in liver diseases treatments.