INTRODUCTION: Nanotechnology is the technology of diagnosing, treating, and preventing diseases using nanoscale structured materials. Zinc oxide nanoparticles (ZnO NPs) have useful effects for their less environmental hazards and for their application usages: tooth pastes, biomedicine and food as zinc supplements. On the other hand, ZnO NPs have toxic effect due to their tissue accumulation ability. Quercetin (Qc) is an antioxidant, categorized as a flavonol. Its beneficial effects are attributed to its phenolic hydroxyl groups. It has antioxidant and antiinflammatory activities. OBJECTIVES: To evaluate the effect of ZnO NPs on rat parotid salivary glands and to investigate the possible protective role of Qc. MATERIALS AND METHODS: Twenty-four adult male albino rats were divided into three equal groups: group (I) control, group (II) received ZnO NPs 300 mg/kg and group (III) received ZnO NPs 300 mg/kg + Qc 200 mg/kg for 28 days. At the end of the experiment, animals were euthanized and the parotid glands were dissected out. The effect of ZnO NPs on the parotid glands as well as the protective role of Qc were assessed by transmission electron microscopy. RESULTS: In group(II) the acinar cells showed signs of toxicity as apoptotic nuclei, degenerated mitochondria, dilated rough endoplasmic reticulum and vacuolization in the cytoplasm. Group (III) parotid glands exhibited remarkable improvement in the ultrastructure of their acinar cells and duct system. This appearance was near to that of control group. CONCLUSIONS: The study proved ZnO NPs toxicity and revealed that oral administration of Qc effectively prevented the toxicity associated with ZnO NPs administration in rat models. Thus, Qc might be used as a prophylactic treatment to prevent ZnO NPs toxicity.