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 exposureon 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: Group I (negative control); Group II (crocin-treated group; 30mg/kg body weight (BW) intraperitoneal (IP) crocin daily); Group III (CUONP-treatedgroup; 0.5-mg/kg BW IP CUONP daily); and Group IV (CUONP/crocin-treated group). After 14 days of the experiment, venous blood samples were collected to determine red blood cell (RBC), white blood cell (WBC), and hemoglobin (Hb) levels. Besides, serum malondialdehyde (MDA), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured. Cerebellar tissue samples were examined under light and electron microscopy along with a histomorphological analysis. CUONPs induced oxidative/antioxidative imbalance as evidenced by a significant increase in serum MDA levels and decreased GPx and TAC activities. CUONPs caused a significant decrease in RBC and Hb levels and an increase in WBC count. Histopathological alterations in the cerebellar cortex were observed. The 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 induced by CUONPs.