To explore the curative effect of citicoline-assisted hyperbaric oxygen on patients with acute cerebral hypoxia induced by carbon monoxide (CO) poisoning and its influences on levels of serum copeptin, S100B protein and glial fibrillary acidic protein (GFAP).Methods A retrospective analysis was performed on the general clinical data of 106 patients with acute cerebral hypoxia induced by CO poisoning treated in the hospital from December 2017 to January 2021. According to different treatment methods, they were divided into control group (n=49, hyperbaric oxygen) and observation group (n=57, citicoline-assisted hyperbaric oxygen). The curative effect between the two groups was compared. The changes in serum copeptin, S100B protein, GFAP, neurological damage, activities of daily life, myocardial damage indexes and hemorheology indexes after treatment in both groups were recorded. The occurrence of adverse reactions was observed. Results The response rate of treatment in observation group was significantly higher than that in control group (98.25% vs 87.76%) (P＜0.05). After treatment, NDF score was significantly decreased, while BI was increased in both groups. After treatment, NDF score in observation group was lower than that in control group, while BI was higher than that in control group (P＜0.05). After treatment, cTnT, CK-MB and AST in both groups were significantly decreased, which were significantly lower in observation group than control group (P＜0.05). After treatment, whole blood high-shear viscosity, whole blood low-shear viscosity and plasma viscosity in both groups were significantly decreased, which were significantly lower in observation group than control group (P＜0.05). After treatment, levels of serum copeptin, S100B protein and GFAP in both groups were significantly decreased, which were significantly lower in observation group than control group (P＜0.05). The incidence of adverse reactions in observation group was slightly higher than that in control group, but the difference was not statistically significant (P＞0.05). Conclusion Curative effect of citicoline-assisted hyperbaric oxygen is significant on patients with acute cerebral hypoxia induced by CO poisoning, which can significantly reduce neurological damage and myocardial damage, improve quality of life and hemorheology indexes. Its mechanism may be related to reducing levels of copeptin, S100B protein and GFAP