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Older age consistently relates to a lesser ability to fully recover from a traumatic brain injury (TBI); however, there is limited data to explicate the nature of age-related risks. This study was undertaken to determine the relationship of age on gene-activity following a TBI, and how this biomarker relates to changes in neuroimaging findings. A younger group (between the ages of 19-35 years), and an older group (between the ages of 60-89 years) were compared on global gene-activity within 48 hours following a TBI, and then at follow-up within 1-week. At each time-point gene-expression profiles, and imaging findings from magnetic resonance imaging (MRI) and computed tomography (CT) were obtained and compared. The younger group was found to have greater gene expression of inflammatory regulatory genes at 48 hours and 1 week in genes such as basic leucine zipper transcription factor 2 (BACH2), leucine rich repeat neuronal 3 (LRRN3) and lymphoid enhancer-binding factor 1 (LEF1) compared to the older group. In the older group, there was increased activity in genes within S100 family, including calcium binding protein P (S100P) and S100 calcium binding protein A8 (S100A8), which previous studies have linked to poor recovery from TBI. The older group also had reduced activity of the noggin (NOG) gene, which is a member of the transforming growth factor-β (TGF-β) superfamily and is linked to neuro-recovery and neuro-regeneration compared to the younger group. We link these gene-expression findings that were validated to neuroimaging, reporting that in the older group with a MRI finding of TBI related damage, there was a lesser likelihood to then have a negative MRI finding at follow-up compared to the younger group. Together, these data indicate that age impacts gene activity following a TBI, and suggests that this differential activity related to immune regulation and neuro-recovery contributes to a lesser likelihood of neuronal recovery in older patients as indicated through neuroimaging.