Copper oxide nanomaterials are used in many biomedical, agricultural, environmental, and industrial sectors with potential risk to human health and the environment. The present study was conducted to determine the renal ultrastructural damage caused by 25 nm CuO nanoparticles in renal tissues. Adult healthy male Wister Albino rats ( Rattus norvegicus) were administered 35 intraperitoneal injections of CuO nanoparticles (2 mg/kg). Ultrastructural changes were evaluated using transmission electron microscopy techniques. The renal tissues of rats with subchronic exposure to CuO nanoparticles demonstrated glomerular alterations that included hypertrophic endothelial cells, dilated capillaries and occlusions, podocyte hypertrophy, pedicle disorganization, mesangial cell hyperplasia, and crystalloid precipitation. Moreover, the treated renal cells exhibited mitochondrial swelling and crystolysis, cytoplasmic vacoulization, lysosomal hypertrophy, apoptotic activity, endoplasmic reticulum dilatation, nuclear deformity, chromatin dissolution, and basement membrane thickening. In addition, disruption and disorganization of the renal cells microvilli together with cystolic inclusions were also detected. It was concluded from the present findings that CuO nanoparticles could interact with the components of the renal tissues in ways that could cause ultrastructural injury, suggesting renal tissue pathophysiology. Additional studies are suggested for a better understanding the nanotoxicity of CuO nanomaterials.