Copper oxide nanoparticles are widely used as semiconductors and in antibacterial medications. They have been reported to elicit various adverse effects including oxidative stress and DNA damage. Vitamin E has been reported to protect against lipid peroxidation induced tissue damage. The aim of this work was to investigate the short term chronic pulmonary toxicity, neurotoxicity and genotoxicity of copper oxide nanoparticles and evaluate the protective role of vitamin E against CuO NPs toxicity in adult male albino rats. Seventy two adult male albino rats were used in this study. They were divided into 5 groups: Negative control group (I), Positive control group (II) subdivided into 2 groups: (IIA) and (IIB), Vitamin E treated group (III), CuO NPs treated group (IV) and CuO NPs + vitamin E treated group (V). After 4 and 8 weeks, 6 rats from each group subjected to blood sample collection for estimating MDA. The rats were sacrificed and the brain and lungs were dissected and divided into three parts. The first part was used for estimating copper content in the brain and lungs. The second part was used to determine the extent of DNA damage. The third part was subjected to microscopic histopathological, and immunohistochemical examination. The results revealed that CuO NPs administration induced a significant increase in serum MDA and in copper content in the brain and the lungs. CuO NPs produced DNA damage and histopathological alteration in the brain and the lungs with increased caspase 3 immunoreactivity. Vitamin E produced improvement in serum MDA, histopathological changes and caspase 3 immunoreactivity with protective effects against DNA damage. From the above mentioned results, it can be concluded that: CuO NPs induced toxic effects and DNA damage in the brain and the lungs and administration of vitamin E with CuO NPs offers protection against their damaging effect.