Brain and systemic inflammation play a role in the vulnerability to, aggravation of, and perpetuation of adverse consequences of traumatic brain injury (TBI). Evidence suggests that elevations in proinflammatory markers, such as interleukin (IL)-6 and C-reactive protein (CRP), within the first 24 hours post-trauma, lead to worse outcomes post-TBI. Following acute TBI, cerebral inflammatory responses begin within minutes, and include elevations of IL-1β, IL-6, IL-8, and tumor necrosis factor alpha (TNFα). The increase in cerebral inflammatory response, including microglial and astroglial activation, is prolonged, lasting months or years, and contributes to the evolving symptomatology and pathology, thereby highlighting inflammation as a potential treatment target long after the acute trauma. TBI also induces secondary changes that lead to delayed neuroinflammation, neuronal cell death, impaired neurological function, and systemic inflammation. These inflammatory responses can also alter the human microbiome, reducing microbial diversity and potentially exacerbating physical and psychological symptoms.