Silver nanoparticles (AgNPs) are extensively used in many industries due to their superior antimicrobial properties. However, it is evident from many studies that AgNPs has cytotoxic potential through its effect on excessive formation of reactive oxygen species (ROS). The aim of this study was to examine the toxic effect of AgNPs on the submandibular salivary glands and the attenuating effect of vitamin E, as a natural antioxidant, against this toxicity. Thirty Albino rats were divided into 3 groups (n = 10): control group, AgNPs group receiving 2 mg/kg daily for 28 days, and AgNPs and vitamin E group receiving AgNPs the same as the previous group in addition to vitamin E at a dose of 100 mg/kg. Microscopic, ultrastructural, and cytokeratin immune-reactivity examination of the glands were performed. The AgNPs group showed noticeable degeneration in all structures of the gland as evident in the histological and ultrastructural examination. The AgNPs and vitamin E group revealed an improvement of the glandular elements. A significant increase in cytokeratin immune expression was found after comparison of both groups (p = 0.01). This current study shows that vitamin E has powerful antioxidant properties, which can combat the cytotoxic effect caused by AgNPs. Further studies are deemed necessary to confirm this finding using other immunohistochemical markers, such as myosin and E-cadherin.