The use of copper oxide nanoparticles (CUONPs) on a large-scale application is a reason for many health problems and morbidities involving most body tissues, particularly those of the nervous system. Crocin is the chemical ingredient primarily responsible for the color of saffron. It has different pharmacological effects, such as antioxidant, anticancer, and memory-improving activities. This study was conducted to elaborate the effects of CUONP exposure on the cerebellar cortical tissues of rats and explore the potential protecting role of crocin through biochemical, light microscopic, and ultrastructural examinations. Twenty four adult male albino rats were randomly divided into four equal groups. Histopathological alterations in the cerebellar cortex were observed. Administration of crocin showed some protection against the toxic effects of CUONPs. Crocin is suggested to have a mitigating role on oxidative stress and structure alterations in the cerebellar tissues.