Background: Nanoparticles (NPs) are used in a wide range in different fields for example cosmetics, manufacturing of clothing, personal care products, and sun protective creams. Diagnosis, imaging, and drug delivery are also considered very important fields using nanoparticles. Zinc oxide (ZnO) NPs is considered one of the greatest frequently used nanoparticles. As ZnO NPs are the furthermost consumed nanomaterials in numerous user products, various scientific works have shown the toxic hazards of ZnO NPs in numerous body systems. Aim: The aim of this work was to detect some of the toxic effects of Zinc oxide nanoparticles and also, to elucidate the protective role of vitamin E (vit E) on stomach and pancreatic cells of adult male albino rats. Material and methods: Zinc oxide (ZnO) NPs was administrated orally at dose of (422 mg/kg body weight) (1/20 LD 50) daily for 8 weeks. Serum levels of glutathione and malondialdehyde (MDA) were estimated. Stomach and Pancreas histopathological microscopic examinations were accomplished. Detection of DNA fragmentation was performed. Results: The results after being statistically analyzed and tabulated revealed that oral Zinc oxide nanoparticles administration induced a significant decrease in serum glutathione and significant increase in serum MDA. It also induced severe histopathological alterations in stomach and pancreatic cells with DNA fragmentation. Administration of vitamin E in addition to zinc oxide NPs induced a significant increase in serum glutathione and a significant decrease in serum MDA, also stomach and pancreatic cells showed mild histopathological changes. Also, vitamin E administration suppressed apoptosis and DNA fragmentation. Conclusion: It was concluded that oral zinc oxide nanoparticles administration induced oxidative stress and destructive genotoxic effects in the stomach and pancreatic cells, and vitamin E administration during exposure to zinc oxide nanoparticles may offer protection against their damaging effect. Recommendations: Zinc oxide nanoparticles caused a potential risk for a series of crucial damage, so zinc oxide nanoparticles exposure either occupationally or dietary must be restricted. Also, raising the awareness among population about its hazardous effects and at the same time, about the potential beneficial effect of vitamin E administration.