Titanium Dioxide Nanoparticles (TiO2NPs) is used in the production of food colorants, some nutritional supplements and many other products on large scale. Many studies stated that the TiO2NPs are more toxic than titanium dioxide (TiO2) and as possibly carcinogenic to humans. The aim of study was carried out to investigate the impacts of vitamin C and vitamin E on free radicals and antioxidant enzymes activities in male rats treated with TiO2NPs. The obtained results showed that, there were no significant (P≥0.05) differences found in red blood cells (RBC), hematocrit (Ht), hemoglobin (Hb) and platelets count (PLT) after treated with titanium dioxide nanoparticles (TiO2NPs) or natural antioxidants (vitamin E and C). The treatment with TiO2NPs alone caused significant (P≤0.05) increase in kidney and liver functions, while the oral intake of V.C and V.E or V.C+V.E reduced this increase. Also, the treatment with TiO2NPs increased the level of free radicals and decreased the activity of some antioxidant enzymes such as Superoxide dismutase (SOD), Glutathione-S-transferase (GST) and the content of Glutathione (GSH) in plasma. Meanwhile, V.C and V.E decreased the increased in free radicals and protected the activity of antioxidant enzymes in plasma of TiO2NPs- treated rats.