Background: Titanium dioxide (TiO₂), consisting of nanoparticles and sub-microparticles, were widely used as food additive and consumed by people every day, which has aroused a public safety concern. Some studies showed TiO₂ can be absorbed by intestine and then distributed to different tissues after oral intake, which is supposed to affect the content of various elements in the body whereas led to tissue damage. However, knowledge gaps still exist in the impact of TiO₂ on the disorder of elemental homeostasis. Thus, this study aimed to explore the oral toxicity of TiO₂ by assessing its influence on elemental homeostasis and tissues injury. Method: ICR mice were fed with normal feed, TiO₂ nanoparticles (NPs)-mixed feed or TiO₂ submicron particles (MPs)-mixed feed (1% mass fraction TiO₂ NPs or MPs were mixed in commercial pellet diet) for 1, 3, and 6 months. Particles used in this study were characterized. The distribution of Ti and other 23 elements, the correlation among elements, and pathological change in the liver, kidney, spleen and blood cells of the mice was determined. Result: Ti accumulation only appeared in blood cells of mice treated with TiO₂ MPs-mixed feed for 6 months, but TiO₂ cause 12 kinds of elements (boron, vanadium, iron, cobalt, copper, zinc, selenium, sodium, calcium, magnesium, silicon, phosphorus) content changed in organ tissue. The changed kinds of elements in blood cells (6 elements), liver (7 elements) or kidney (6 elements) were more than in the spleen (1 element). The TiO₂ NPs induced more elements changed in blood cells and liver, and the TiO₂ MPs induced more elements changed in kidney. Significantly positive correlation between Ti and other elements was found in different organs except the liver. Organ injuries caused by TiO₂ NPs were severer than TiO₂ MPs. Liver exhibited obvious pathological damage which became more serious with the increase of exposure time, while kidney and spleen had slight damages. Conclusion: These results indicated long-time dietary intake of TiO₂ particles could induce element imbalance and organ injury. The liver displayed more serious change than other organs, especially under the treatment with TiO₂ NPs. Further research on the oral toxicity of TiO₂ NPs should pay more attention to the health effects of element imbalances using realistic exposure methods.