Objective To investigate the effect of hyperbaric oxygen (HBO) therapy on serum copeptin level in patients with severe traumatic brain injury and its clinical significance.Methods A total of 76 patients with severe traumatic brain injury were randomly divided into control group and experimental group. The patients in the experimental group were given HBO therapy in addition to the conventional treatment in the control group. The two groups were compared in terms of serum copeptin level at weeks 1, 2, and 3 of HBO therapy or conventional treatment and change in Glasgow Coma Scale (GCS) score after treatment.Results Compared with the control group, the experimental group had a significant reduction in serum copeptin level at weeks 1, 2, and 3 of HBO therapy (P<0.05). After 3 weeks of treatment, both groups had a significant increase in GCS score (P<0.05), and the experimental group had a significantly greater increase than the control group (aP<0.05).Conclusions In patients with severe traumatic brain injury, HBO therapy can reduce serum copeptin level and promote rehabilitation, and the rehabilitation of such patients promoted by HBO therapy may be associated with the reduction in serum copeptin level after HBO therapy.