Post-traumatic headache (PTH) is one of the most frequent and persistent physical symptoms following mild traumatic brain injury (mTBI). However, the underlying neurobiological basis and modulatory component remained unclear. Evidence indicated that neuroinflammation is a major contributor in the pathogenesis of PTH. We hypothesized that the effect of peripheral inflammatory signaling on PTH could be produced by influencing brain structure that subserve pain modulatory function. Our findings demonstrated that neuroinflammation following mTBI is a potential process affecting structural changes in cognitive component of pain modulation, which may serve as a potential neurobiological mechanism underlying the emergence and persistence of PTH.