<p>Pain is a complex physiological process that can affect quality of life if it becomes chronic. Additionally, conventional analgesic drugs have long-term side effects. Recently, nanotechnology has been applied to the diagnosis and treatment of various diseases, and nanotechnology-based drug delivery has provided promising results in pain management. Zinc oxide nanoparticles (ZnO NPs) have gained attention in biomedical fields due to their unique physicochemical properties, which enhance their interaction with biological system. Currently, researchers have focused on the optimization and modification of ZnO NPs for medical usage. These nanoparticles can cross the blood–brain barrier and influence both histological and biochemical parameters of the nervous system. Several animal studies have evaluated their effects on pain perception, particularly focusing on brain regions like the hippocampus. ZnO NPs at low doses and in the acute phase have been reported to exert analgesic effects without causing neurotoxicity. Also, the effects of ZnO NPs have been studied in neurological behavior in animal’s models. In this review paper, we evaluated the ZnO NPs effects by examining the histological and biochemical alterations in brain tissue, specifically the hippocampus, and their underlying mechanisms related to pain management.</p> Graphical abstract <p></p>