Continuous exposure to CuO NPs resulted in significantly increased MDA levels and decreased overall antioxidant capacity, associated with remarkable pathological changes in all brain regions, including the cerebellum, hippocampus, and cerebellum. Continuous exposure to CuO nanoparticles resulted in overexpression of the immunohistochemical markers caspase-3, iNOS and GFAP as well as DAN fragmentation and downregulation of HO-1 and Nrf2 genes in brain tissues. Neuropathological and cognitive effects induced by CuO-NPs in rats and prophylactic experiments with pomegranate juice. Progressive memory impairment as well as cognitive and psychiatric disorders were observed in CuO-NP-treated mice but not in PJ-treated mice. We have shown that PJ has the ability to reduce damage from oxidative stress by up-regulating HO-1 and Nrf2 genes in the brain. Our experiment aims to investigate the neurobehavioral and toxicopathological effects of CuO-NP and to explain the mechanistic role of PJ in reducing toxicity. In contrast, mice treated concomitantly with PJ showed dose-dependent improvement in toxicological, behavioral, and general pathological parameters. Before undergoing any natural, integrative, or conventional treatment, it is advisable to seek the advice of a licensed health care professional. By providing the information contained herein, we are not diagnosing, treating, curing, alleviating or preventing any disease or illness. Pomegranate, its components and modern dosage forms as potential herbs in the prevention and treatment of various cancers. Such overexposure raises concerns about possible toxic effects on humans and animals. Over 500 pages of information on natural alternative remedies.