Fluoride (F), one of the most toxic environmental and industrial pollutants, is known to exert hepatotoxicity. The contribution of oxidative stress to the F tolerance of liver remains largely unknown. In this study, the morphological and ultrastructural characteristics of liver were observed using hematoxylin and eosin staining and transmission electron microscopy (TEM), respectively. Oxidative-stress participations was analysed and the mRNA expression levels of catalase (Cat), glutathione peroxidase 1 (GSH-Px1), nitric oxide synthase 2 (NOS2), and superoxide dismutase 1 (SOD1) were investigated by real-time PCR. Changes in liver-function parameters were also detected. Results showed that the reactive content of reactive oxygen species increased significantly, whereas SOD and GSH-Px activities, as well as total anti-oxidising capability (T-AOC), decreased significantly, with increased nitric oxide (NO) and malondialdehyde (MDA) contents in liver and serum after 70days of F treatment. The mRNA expression levels of Cat, GSH-Px1, and SOD were significantly downregulated, whereas NOS2 mRNA expression level was up upregulated, after F treatment for 70days. Light microscopy also revealed that hepatocytes were fused into pieces; cell boundaries were unclear, and nuclei were lightly stained. TEM further showed that hepatocytes were characterised by vague nuclear and mitochondrial membranes, dilated endoplasmic reticulum, and aggravated vacuolar degeneration. Activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase, as well as the level of total bilirubin in serum increased. Overall, these results indicated that F interfered with the balance of antioxidase activity and morphological changes in liver, which were involved in mouse liver dysfunction.