Ischaemia and metabolic dysfunction remain important causes of neuronal loss following head injury, and we have shown that normobaric hyperoxia may rescue such metabolic compromise. This study examines the impact of hyperoxia within injured brain using diffusion tensor imaging (DTI). Fourteen patients underwent DTI at baseline and following one hour of 80% oxygen. Using the apparent diffusion coefficient (ADC) we assessed the impact of hyperoxia within contusions and a 1 cm border zone of normal appearing pericontusion, and within a rim of perilesional reduced ADC consistent with cytotoxic oedema and metabolic compromise. Seven healthy volunteers underwent imaging at 21%, 60% and 100% oxygen. In volunteers there was no ADC change with hyperoxia, and contusion and pericontusion ADC values were higher than volunteers (p < 0.01). There was no ADC change following hyperoxia within contusion, but an increase within pericontusion (p < 0.05). We identified a rim of perilesional cytotoxic oedema in 13 patients, and hyperoxia resulted in an ADC increase towards normal (p = 0.02). We demonstrate that hyperoxia may result in benefit within the perilesional rim of cytotoxic oedema. Future studies should address whether a longer period of hyperoxia has a favourable impact on the evolution of tissue injury.