The aim of the present study was to was investigate the treatment efficacy of hyperbaric oxygen (HBO) combined with nimodipine on diffuse brain injury. AA total of 80 patients with diffuse brain injury were randomly divided into four groups: Group A, conventional treatment; Group B, conventional treatment + nimodipine; Group C, conventional treatment + HBO therapy and Group D, conventional treatment + nimodipine + HBO therapy. The Glasgow Coma Scale (GCS) score and serum tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were assessed before treatment and at 8, 24, 48 and 72 h after treatment. The bilateral middle cerebral arterial blood flow velocity (VmMCA) was measured by transcranial Doppler ultrasound. The results indicated that serum TNF-α and IL-1β were significantly decreased in all groups at 24, 48 and 72 h after treatment, compared with 8 h after treatment (P<0.05), with Group D exhibiting the largest decrease. The serum TNF-α, IL-1β and VmMCA peaked at 8 h and gradually decreased over the treatment period. VmMCA was decreased in Group B and D compared with Group A and C, and the decrease rate was higher in Group D compared with Group B (P<0.05). GCS scores were significantly increased in all groups at 24, 48 and 72 h after treatment compared with 8 h after treatment (P<0.05), with Group D exhibiting the largest increase. Serum TNF-α and IL-1β levels were positively correlated with VmMCA (P<0.05) and negatively correlated with GCS (P<0.05). Punctate hemorrhage was observed in all groups on CT before treatment, with a value of 66±3 HU. Punctate hemorrhage was observed to decrease over time in CT images, and CT values were significantly decreased in all groups at 8, 24, 48 and 72 h compared with before treatment (P<0.05). CT values were significantly lower in group D compared with groups A, B and C (P<0.05) at all time points. Serum TNF-α and IL-1β levels were positively correlated with CT value (P<0.05). In conclusion, HBO combined with nimodipine exhibited increased efficacy in the treatment of brain injury compared with either treatment alone.