The secondary phase of traumatic brain injury (TBI) is partly caused by the release of excess reactive oxygen species (ROS) from the primary injury. However, there are currently no therapies that have been shown to reduce the secondary spread of injury beyond the primary insult. Nanoparticles offer the ability to rapidly accumulate and be retained in injured brain for improved target engagement. Here, we utilized systemically administered antioxidant thioether core-cross-linked nanoparticles (NP1) that scavenge and inactivate ROS to reduce this secondary spread of injury in a mild controlled cortical impact (CCI) mouse model of TBI. We found that NP1 treatment protected CCI mice from injury induced learning and memory deficits observed in the Morris water maze (MWM) test at 1-month post-CCI. This protection was likely a result of NP1-mediated reduction in oxidative stress in the ipsilateral hemisphere as determined by immunofluorescence imaging of markers of oxidative stress and the spread of neuroinflammation into the contralateral hippocampus as determined by immunofluorescence imaging of activated microglia and neuron-astrocyte-microglia triad formation. These data suggest NP1-mediated reduction in post-traumatic oxidative stress correlates with the reduction in the spread of injury to the contralateral hippocampus to protect spatial memory and learning in CCI mice. Therefore, these materials may offer an improved treatment strategy to reduce the secondary spread of TBI.