In recent years, the noble gas argon (Ar) has been extensively studied for its organ protection properties. While mounting in vitro and in vivo evidence indicates that argon provides neuroprotection in ischemic brain injury, its neuroprotective potential in traumatic brain injury (TBI) has not been evaluated in vivo. We tested the hypothesis that prolonged inhalation of 70% or 79% argon for 24h after closed-head injury (CHI) improves neurologic outcome and overall recovery at 36days post-injury. We also compared effects of the 30% or 21% residual oxygen on argon's potential neuroprotective capacity. Adult male C57/black mice (n = 240) were subjected to closed-head traumatic brain injury, followed by inhalation of 70% argon or nitrogen (30% oxygen), or 79% argon or nitrogen (21% oxygen) for 24h. Neurologic outcome (rotarod, neuroscore, and Morris water maze) was evaluated for up to 36days post-injury. Histologic parameters of neurologic degeneration (Fluoro-Jade staining) and inflammation (F4/80 microglia immunostaining) were assessed in subgroups at 24h and on post-injury day 7. Our CHI protocol consistently resulted in significant brain injury. After argon inhalation for 24h at either concentration, mice did not show significant improvement with regard to neuroscores, rotarod performance, Morris water maze performance, or overall recovery (body weight), compared to nitrogen controls, up to 36days. At 7days post-injury, histologic markers of neurodegeneration and inflammation, particularly in the hippocampus, consistently demonstrated significant injury. Notably, recovery was reduced in mice treated with the higher oxygen concentration (30%) after CHI compared to 21%. Prolonged argon treatment did not improve neurologic outcome, overall recovery (weight), nor markers of neurodegeneration or neuroinflammation after significant CHI compared to nitrogen. While neuroprotective in predominately ischemic injury, argon did not provide protection after TBI in this model, highlighting the crucial importance of assessing argon's strengths and weaknesses in preclinical models to fully understand its organ protective potential in different pathologies and gas mixtures.