Traumatic brain injury (TBI) is a leading cause of morbidity and mortality around the world. It has multiple causative factors including sports injuries, vehicular accidents, war, and other forms of trauma. Though patients can recover, it has the potential to cause mild to severe persistent cognitive deficits. Medical treatment involves treating individual problems as they arise; this treatment is based upon clinical signs. Developing a standard of care for TBI is complex due to the difficulty in finding common cell and molecular changes in TBI variants that can be prevented or ameliorated. Tumor necrosis factor (TNF) is a prominent inflammatory cytokine present in all forms of traumatic brain injury. It is the target of multiple therapies in other disease processes. As TNF inhibitors lead to billions of dollars in worldwide sales, their use in neuropathologies is an active research area. XPro1595, a preclinical drug developed by Xencor, uniquely inhibits more than 99% of soluble TNF. However, there is only one published study to date on the effects of XPro1595 in any model of traumatic brain injury. The purpose of this study was to characterize the presence of TNF and the proinflammatory TNFR1 pathway in a controlled cortical impact (CCI) mouse model of TBI and to determine if XPro1595 could improve behavioral and neuropathological outcomes. TNF and the TNFR1 pathway have shown to be chronically present in a CCI mouse model for at least two weeks. Injured animals treated with one course of the drug did not show any improvements in spatial learning or memory. However, decreased activity in the TNFR1 pathway and changes in glial markers indicated that XPro1595 lessened neuroinflammation via this mechanism. This study suggests potential benefits of XPro1595 in TBI that could lead to a common standard of care.