The purpose of this study was to evaluate the hepatoprotective effect of an antioxidative nanoparticle (RNP(N)) recently developed against APAP-induced hepatotoxicity in mice. The effects of oral administration of RNP(N) to APAP-treated mice were assessed for various biochemical liver function parameters: alanine transaminase (ALT) activity, aspartate transaminase (AST) activity, alkaline phosphatase (ALP) activity, prothrombin time, and serum albumin (ALB) level. The treatment effects were assessed in terms of free radical parameters: malondialdehyde (MDA) accumulation, glutathione peroxidase (GPx) activity, % inhibition of superoxide anion (O2 (-∙)), and histopathological examination. The N-acetylcysteine (NAC)-treated group exhibited an enhanced prothrombin time relative to the control group, while RNP(N) did not prolong prothrombin time. The RNP(N)-treated animals exhibited lower levels of ALT, AST, and ALP, while increased ALB levels were measured in these animals compared to those in the other groups. The RNP(N)-treated animals furthermore exhibited improved MDA levels, GPx activity, and % inhibition of O2 (-∙), which relate to oxidative damage. Histological staining of liver tissues from RNP(N)-treated animals did not reveal any microscopic changes relative to the other groups. The findings of this study suggest that RNP(N) possesses effective hepatoprotective properties and does not exhibit the notable adverse effects associated with NAC treatment.