Zinc oxide nanoparticles (ZnO NPs) are widely used in industry and cosmetic products with promising investment in medical diagnosis and treatment. However, these particles may reveal high potential risk for human health with little information is available about their toxicity. The present study was carried out to investigate the ultrastrcutural alterations induced in the hepatic tissues by ZnO NPs. Male Wistar albino rats were exposed to ZnO NPs at a daily dose of 2 mg/kg for 21 days. Furthermore, liver biopsies from all rats under study were subjected and processed for transmission electron microscopy and ultrastructural examination. Exposure to ZnO NPs has induced the following ultrastructural alterations: sinusoidal dilatation, Kupffer cells enlargement and activation, mitochondrial crystolysis and swelling, endoplasmic reticulum dilatation and vesiculation, myelin figures formation, karyopyknosis, nuclear membrane irregularity, chromatin fragmentation and glycogen depletion. These findings may suggest that ZnO NPs can induce ultrastructural alterations in the hepatic tissues resulted from disturbance of the pro-oxidant/antioxidant system leading to cellular alterations and affecting the liver functions. The results raise the concerns about the safety associated with ZnO NPs applications and highlight on the need to elucidate probable nanotoxicity that might be induced by these particles in the vital organs.