Acute carbon monoxide (CO) poisoning may cause liver damage and liver dysfunction. Therefore, in this study, we aimed to compare the efficiency of normobaric oxygen (NBO) and high-flow nasal cannula oxygen (HFNCO) treatments on liver injury. For that purpose, 28 male Wistar albino rats were divided into four groups (Control, CO, CO + NBO, and CO + HFNCO). The control group was allowed to breath room air for 30 min. Acute CO poisoning in CO, CO + NBO, CO + HFNCO was induced by CO exposure for 30 min. Thereafter, NBO group received 100% NBO with reservoir mask for 30 min. HFNCO group received high-flow oxygen through nasal cannula for 30 min. At the end of the experiment, all animals were sacrificed by cardiac puncture under anesthesia. Serum liver function tests were measured. Liver tissue total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels, tissue histomorphology and immunoexpression levels of Bax, Caspase 3, TNF-α, IL-1β, and NF-κB were also examined. Our observations indicated that acute CO poisoning caused significant increases in blood COHb, serum aminotransferase (AST), alanine aminotransferase (ALT0, alkaline phosphatase (ALP), total protein, albumin, and globulin levels but a decrease in albumin to globulin ratio (all, p < 0.05). Furthermore, acute CO poisoning significantly increased the OSI value, and the immunoexpresssion of Bax, Caspase 3, TNF-α, IL-1β, and NF-κB in liver tissue (all, p < 0.05). These pathological changes in serum and liver tissue were alleviated through both of the treatment methods. In conclusion, both the NBO and HFNCO treatments were beneficial to alleviate the acute CO poisoning associated with liver injury and dysfunction.