Traumatic brain injury (TBI) is the leading cause of disability and death in children and adults under 45, with approximately ten million new cases per year worldwide. Significant progress has been made in understanding the complex pathophysiological response to TBI; however, reducing the damage associated with the reactive oxygen species (ROS)-dependent secondary phase of the injury remains a substantial challenge. The development of an image-guided, Gd-conjugated, oxygen reactive polymer (ORP) to reduce ROS levels in damaged brain tissue is reported. ORP effectively sequesters ROS while remaining biocompatible even at elevated concentrations. ORP is retained in damaged brains of controlled cortical impact (CCI) mouse models of TBI for over 24 h when injected intravenously immediately and up to 3 h post-CCI. The polymer reduces neurodegeneration tenfold and gliosis twofold in these mouse models. ORP shows initial promise as an effective therapy for TBI and helps provide a better understanding of nanomaterial interaction with damaged brain.