Background <p>To assess the impact of titanium dioxide nanoparticles (TiO₂NPs) on submandibular salivary glands and the role of vitamin E in preventing this cytotoxicity.</p> Methods <p>Thirty adult male albino rats were randomly divided into 3 groups: Negative control received olive oil for 3 weeks; Study I received olive oil for 1 week, then daily oral administration of 300&#xa0;mg/kg TiO₂NPs for 2 weeks; and Study II received 100&#xa0;mg/kg vitamin E diluted in 100&#xa0;ml olive oil daily as a prophylactic from day 1 for 3 weeks. On day 8, with vitamin E, they received 300&#xa0;mg/kg TiO₂NPs for 2 weeks by oral gavage. All samples were examined via hematoxylin &amp; eosin (H&amp;E), histomorphometry of serous acinar surface areas, transmission electron microscopy (TEM), and blood analysis of malondialdehyde (MDA) and interleukin (IL-1β) levels.</p> Results <p>Serum levels of both MDA and IL-1β were significantly greater in study I than in control and study II groups. Histologic examination revealed structural changes in serous acini and ducts of study I, with great preservation of the normal appearance of the acini and ducts in study II. Histomorphometry revealed a significant difference between control and study I, with no significant difference from that in study II. TEM revealed multiple ultrastructural changes in acinar cells and ducts of study I compared with those of study II, which maintained their normal features.</p> Conclusions <p>Vitamin E plays crucial antioxidant and anti-inflammatory roles in counteracting the cytotoxic effects of TiO₂NPs by alleviating their deleterious impact on salivary glands.</p>