Objective To investigate the effect of hyperbaric oxygen therapy on Toll-like receptor 4 (TLR4) / nuclear factor kappa B (NF-κB) signaling pathway and the prognosis in patients with delayed encephalopathy after carbon monoxide poisoning (DEACMP).Methods The 90 DEACMP patients treated in our hospital from October 2018 to October 2019 were selected and randomly divided into the experimental group and the control group. The control group was given conventional treatment, while the experimental group was treated with hyperbaric oxygen therapy on the basis of the conventional treatment. The clinical efficacy, the levels of TLR4 mRNA and NF-κB p65, Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score, Activities of Daily Living (ADL) score, and age-related white matter changes (ARWMC) rating scale score before and after the treatment, and the modified Rankin Scale (mRS) score at 3, 6 and 12 months after the treatment were compared between the two groups.Results The overall effective rate of the observation group was higher than that of the control group (P < 0.05). The differences of the relative expression of TLR4 mRNA and NF-κB p65 before and after the treatment in the experimental group were greater than those in the control group (P < 0.05). In addition, the differences of LOTCA and ADL scores before and after the treatment in the experimental group were also greater than those in the control group (P < 0.05), while the difference of ARWMC rating scale score before and after the treatment was lower in the experimental group compared with the control group (P < 0.05). The repeated measures analysis of variances showed that the mRS scores were different at different time points (F = 122.783, P = 0.000) and between the groups (F = 43.885, P = 0.000), and that the change trend of mRS scores between the experimental group and the control group was also different (F = 66.939, P = 0.000).Conclusions Hyperbaric oxygen therapy exhibits high therapeutic efficacy in DEACMP patients, and improves the prognosis of patients by regulating TLR4 / NF-κB signaling pathway.