<p>Traumatic brain injury (TBI) is defined as structural damage or physiological disruption of brain function resulting from mechanisms such as direct impact, rapid acceleration or deceleration, penetrating injury, or exposure to blast waves. These biomechanical insults initiate a complex cascade of secondary injury processes, including neuronal cell death, neuroinflammation, oxidative stress, microglial activation, and blood–brain barrier dysfunction. These events contribute to the loss of homeostasis in both the central and peripheral nervous systems. Importantly, these pathophysiological changes may extend beyond the acute phase, often evolving into chronic conditions that can persist for years after the initial injury. In addition, TBI can cause fractures of the skull base and predispose to CSF leak and CSF fistula, which contribute to the contraction of bacteria. Surgical interventions, invasive devices, and prolonged immobilization are other factors that predispose patients to develop an infection secondary to TBI. Among the infections developed secondarily by patients with TBI are meningitis, pneumonia, and urinary tract infections, which can progress to Systemic Inflammatory Response Syndrome (SIRS) and sepsis. Furthermore, immunosuppression due to the lack of components of the cellular immune response, particularly neutrophils, helper T cells, regulatory T cells, and natural killer (NK) cells, demonstrates the pathophysiological heterogeneity of TBI, which can result in complications involving the central nervous system (CNS) and peripheral nervous system (PNS). Understanding how these secondary infections impact patient prognosis becomes necessary for more individualized therapies for each patient.</p> Graphical Abstract <p></p>