TiO2 nanoparticles (NPs) are used in the food industry but have potential toxic effects in humans and animals. The resulting immune response is driven by the production of Th2 cytokines IL-4 and IL-5, which contribute to the development of hepatic inflammation. However, TiO2 NPs have been demonstrated to impair liver function and cause liver inflammation in animal models, which may be associated with activation of Th2 factor-mediated pathways. Mice were administered a gavage instillation of 2.5, 5, or 10 mg/kg body weight TiO2 NPs for six consecutive months. We investigated whether TiO2 NPs activate the Th2 factor-mediated signaling pathway under TiO2 NP-induced hepatic toxicity. The results showed that mice exhibited an accumulation of titanium in the liver, which in turn led to reductions in body weight, increases in liver indices, liver dysfunction, infiltration of inflammatory cells, and hepatocyte apoptosis or necrosis. Furthermore, hepatic inflammation was accompanied by increased (0.67 ± 0.09- to 2.14 ± 0.19-fold) IL-4 expression and up-regulation of its target genes including IL-5 (0.1 ± 0.06- to 0.69 ± 0.12-fold), IL-12 (0.08 ± 0.03- to 0.83 ± 0.21-fold), IFN-γ (0.17 ± 0.09- to 0.87 ± 0.15-fold), GATA3 (0.05 ± 0.02- to 1.29 ± 0.18-fold), GATA4 (0.04 ± 0.01- to 0.87 ± 0.13-fold), T-bet (0.3 ± 0.06- to 0.93 ± 0.15-fold), RORγt (0.32 ± 0.11- to 1.67 ± 0.17-fold), STAt3 (0.16 ± 0.06- to 2.14 ± 0.23-fold), STAT6 (0.2 ± 0.05- to 0.63 ± 0.12-fold), eotaxin (0.53 ± 0.13- to 1.49 ± 0.21-fold), MCP-1 (0.5 ± 0.11- to 0.74 ± 0.18-fold), and MIP-2 (0.27 ± 0.07- to 0.71 ± 0.18-fold) and significant down-regulation of its target gene STAT1 (-0.15 ± 0.05 to -0.81 ± 0.11-fold). Taken together, the alteration of Th2 factor expression may be involved in the control of hepatic inflammation induced by chronic TiO2 NP toxicity.