Nowadays, titanium dioxide nanoparticles (TiO₂NPs) are widely used by many industries and are present in many products including toothpastes, sweets, and medications. Therefore, humans are exposed to considerable amounts of this material in their daily lives. However, limited studies are available regarding the relationship between the effects of TiO₂NP-induced genotoxicity and the incidence of liver cancer. Therefore, this study was designed to investigate the impact of TiO₂NPs-induced genotoxicity and mutagenicity in the livers of mice. Further, we assessed the development of hepatic cancer in these mice. Oral administration of TiO₂NPs resulted in persistent single and double stranded DNA breaks which were indicated by the fragmented and smeared genomic DNA observed on an agarose gel. This damaged DNA resulted in apoptosis-induced liver damage. Progressive accumulation of TiO₂NPs-induced DNA damage resulted in a high mutation incidence in both the p53 and H-ras genes. Moreover, histological examinations revealed necrosis throughout the liver during the experimental period. This damage could be attributed to the persistent and significant increase in malondialdehyde and reduction in glutathione levels. In conclusion, the accumulation of orally administered TiO₂NPs resulted in persistent DNA damage, apoptosis, and oxidative stress. These events ultimately lead to necrosis in the entire liver, which increased the incidence of hepatocellular carcinoma.