alpha-Phenyl-tert-N-butyl nitrone (PBN), a potent reactive oxygen species (ROS) scavenger, has shown robust neuroprotective properties in several models of acute brain injury, although not previously evaluated in traumatic brain injury (TBI). In this study, we assessed the potential efficacy of PBN in a weight drop model producing a controlled cortical contusion. Sham operation, mild or severe injury was induced in intubated and ventilated rats and functional and morphological outcome was used as end-points at two weeks post-injury. In the trauma groups, saline or PBN (30 mg/kg) was injected as an intravenous bolus 30 minutes prior to injury. At day 11-15 post-injury, cognitive disturbance was assessed using the Morris Water Maze (MWM) and estimation of lesion volume and hemispheric loss of tissue was made. No change in MWM performance were found in either of the mildly traumatized groups as compared to uninjured controls. In contrast, a significant decrease in total mean latency and increase in path length in the severely traumatized rats were found. PBN-treatment significantly improved MWM performance as compared to saline treatment at the severe injury level (p < 0.05). The mild injury level caused a discrete atrophy of the ipsilateral cortex with no effect of PBN treatment. The severe injury caused a substantial loss of ipsilateral hemispheric tissue and a large cortical cavitation. PBN pre-treatment significantly reduced the lesion volume and reduced hemispheric loss of tissue at this injury level (p < 0.05). Our results support the involvement of ROS in the injury process contributing to the tissue loss and cognitive disturbance after TBI. The potential clinical utility of PBN will have to be assessed using a post-injury dosing regime.