Abstract: Background: Titanium dioxide nanoparticles (TiO2NPs) nanoparticles are among the most commonly used metal oxide nanoparticles in industrial products, such as cosmetics, sunscreens, food products, paints and drugs. They have been reported to elicit various adverse cellular effects including oxidative stress and DNA damage. Aim: The aim of this work was to study the toxic effects of oral TiO2NPs and the possible antioxidant protective role of N-acetylecysteiene (NAC) on the liver of adult albino rats. Material and methods: Fifty adult male albino rats were classified into five equal groups. Group I: Negative control received regular diet and water. Group II: Positive control administered 1ml of 5% gum acacia solution (solvent of TiO2) once daily. Group III: Each rat gavaged orally with 100 mg/kg b.w. NAC once daily. Group IV: Each rat received 1200 mg/kg b.w. TiO2NPs in 1ml of 5% gum acacia once daily. Group V: Each rat gavaged orally with 100 mg/kg b.w. NAC then 1200 mg/kg b.w. TiO2NPs once daily. After 12 weeks the rats of all groups were subjected to blood sample for estimating aspartate transaminase (AST), alanine transaminase (ALT), Total bilirubin (TBIL), reduced glutathione (GSH) and serum malondialdehyde (MDA) level. Then the liver was dissected and subjected to histological and ultrastructural examination and immunohistochemical detection of TNF-α. Cell suspension from the liver was examined to determine the extent of DNA damage by the Comet assay. Results: The results revealed that TiO2NPs induced histological and ultrastructral changes in the liver in the form of congestion and lymphocytic aggregation. The hepatocytes were vacuolated with pyknotic nuclei and positive for TNF-α immunoreaction. Also, the oxidative toxic effects of TiO2NPs on liver function were demonstrated through the detection of increased AST, ALT and serum MDA level with decreased in TBIL and GSH level in comparison to controls. Also, commet assay result showed that TiO2NPs exposure produced DNA damage in liver cells. On the other hand administration of NAC with TiO2NPs produced partial to complete protection of hepatic histological changes, TNF-α immunoreactivity, liver function tests and oxidative stress markers with moderate protective effects against DNA damage. Conclusion: TiO2NPs exposure causes toxic effects on the liver that may be attributable to oxidative stress and administration of NAC offers protection against its damaging effects. Recommendations: It is recommended to limit ingestion of TiO2 nanoparticles through nonessential drug additives, food colors, etc. and to decrease the risk of TiO2NPs toxicity, NAC can be used as supplement to occupationally exposed workers.