Background: Titanium dioxide "TiO2, E171″ is a widely used food additive that exists in various everyday food products all over the world together with vast applications in cosmetics and industry. However, many toxicological aspects particularly following oral exposure still unclear. Methods: Hence, this study was planned to examine the effect of oral exposure of male Wistar rats to two doses of TiO2 (20 or 40 mg/kg b.wt.) through oral gavage once daily for 90 consecutive days on the blood components, immunity, cytotoxic, and genotoxic indicators. Results: A dose-dependent leukopenia, eosinophilia, neutrophilia, and thrombocytopenia were noted. Also, the immunoglobins G (IgG) and IgM were significantly elevated in TiO2 treated rats. The phagocytic activities, lysozyme, nitric oxide, and immunoglobulin levels were significantly depleted following TiO2 exposure. A significantly reduced lymphocyte proliferation but elevated LDH activity was prominent in TiO2 treated rats. Different pathological perturbations were observed in both splenic tissue and bone marrow. A marked increase in CD4+ and CD8+ immunolabeling was evident. A significant increase in the comet variables was recorded in response to the exposure of rats to the increasing level of TiO2 at both levels. Conclusion: Overall, these results indicated that TiO2 could induce hematotoxicity, genotoxic, and immunotoxic alterations with exposure for long durations.