Back ground: Zinc oxide nanoparticles (ZnO-NPs) are among the most commonly used metal nanoparticles and are nowadays increasingly used in food. This might increase the chances of their exposure to the human body via the oral route. The heart is an important toxic site for nanoparticles. Aim: The aim of the current study was to investigate the possible histological changes that might accompany the oral administration of two different doses of ZnO-NPs on left ventricular cardiomyocytes of adult albino rats. Materials and Methods: Forty-eight adult male rats were included. The animals were randomly divided into 3 main groups. Group I (Control group). Group II (ZnO-NPs group) was further subdivided randomly into subgroup IIa that were given ZnO-NPs at a dose of 100mg/kg body weight/day. Subgroup IIb received 400 mg/kg body weight/day ZnO-NPs for 28 days. Group III (Withdrawal group), the animals of this group did not receive any treatment for four weeks after the 28 days of treatment. Specimens from the heart apex were processed for microscopic examination. Serum level of oxidative stress and cardiac makers, as well as the morphometric study (for collagen quantification and mitochondrial morphometry), were done. Results: The light and the electron microscopes revealed histological changes in the left ventricular cardiomyocytes. Changes were dose-dependent. Group II revealed some pale stained muscle fibers with pyknotic nuclei. Others showed deeply acidophilic sarcoplasm. The electron microscope examination confirmed these changes and showed focal myolysis and abnormal mitochondria. This was associated with some hyperchromatic nuclei. After withdrawal histological changes were exaggerated. Serum marker of oxidative stress and cardiac markers showed a significant increase. Mitochondrial morphometry demonstrated fragmentation. Conclusion: The study demonstrated that oral ZnO-NPs are associated with variable microscopic changes, which is dosedependent. These changes didn't improve after the withdrawal of the ZnO-NPs administration.