Among the disabling consequences of traumatic brain injury (TBI), post-traumatic headache (PTH) disorder and neuropsychiatric sequelae represent significant co-morbidities in the TBI population. Current data suggests PTH to be associated with a greater risk of evolving into chronic or daily persistent headaches. Preclinical research concerning the pathophysiology of PTH is currently underdeveloped due to a lack of pre-clinical models. We propose that a well-established model of TBI, controlled cortical impact (CCI), represents an effective means by which to study the initiation and chronification of PTH pain. The goal of this study was to investigate mechanisms of central sensitization within the trigeminovascular system in a murine model of CCI injury. Male C57BL/6 mice received either craniotomy (shams) or TBI followed by weekly behavioral testing up to postoperative day 28; na´ve mice were included as controls. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) in the spinal trigeminal tract, as well as glial activation and TNFa protein levels where evaluated using immunohistochemistry and ELISA. Bilateral periorbital cutaneous hypersensitivity was quantified using graded von Frey monofilament testing. Co-morbid factors aggressive and anxiety-like behaviors were also assessed in this study. Our results show TBI induced significantly increased SP immunoreactivity and CGRP levels in the spinal trigeminal tract. TBI mice had significantly increased bilateral periorbital cutaneous hypersensitivity that intensified over time compared to sham and na´ve mice indicating persistent central sensitization. TBI groups showed increased astrocyte and macrophage/microglia immunoreactivity and TNFa protein levels localized to regions containing meningeal nociceptors when compared to sham and na´ve mice. TBI mice showed a significant increase in the number of aggressive behaviors towards a juvenile mouse along with a hyperactivity response compared to sham and na´ve controls. In conclusion, the CCI injury model provides a novel tool to study mechanisms involved in the chronification of PTH pain.