Head injury that results in concussion affects millions of people world-wide each year, and repeated head injury (RHI) is a known risk factor for neurodegenerative disease. How the brain becomes susceptible to acute symptoms or long-term pathology is unclear, and neuroimaging biomarkers are lacking. We propose that the immune response within the meningeal borders of the is key determinant of outcome. We have developed new models of RHI that cause meningeal dysregulation, blood-cerebrospinal fluid (CSF)-barrier breakdown and altered brain function. In this clinically relevant model of a single mild head injury, we found meningeal immuno-matrix dysregulation without brain changes or blood-CSF-barrier breakdown. However, RHI opens the blood-CSF-barrier and causes long-term anxiety-like behaviour and cognitive changes. Blocking regulatory molecule TGF-β drives immune cell accumulation in the cortex, increases microglia activation and prevents adaptive behaviours. In professional athletes with RHI, dynamic contrast enhancement (DCE) MRI of CSF space shows arachnoid associated blood-CSF-barrier breakdown. Together, these results suggest that the physical arachnoid barrier, followed by molecular TGF-β protection, provide a layered defence to head injury, that is overcome by RHI. These data highlight a key role for meningeal immune response in head injury and identify new areas of structural integrity loss, undetectable by standard clinical imaging. Additionally, it opens avenues for neuroimaging biomarker development for those affected by RHI and at risk of neurodegenerative disease.