<p>Traumatic brain injury has a high neurological morbidity, it is characterized by structural and physiological damage to brain function caused by external forces. Extensive and sustained damage mediated by neuroimmune and neuroinflammation may be closely associated with the prolonged course of TBI and the worsening of its prognosis. Tumor necrosis factor-alpha, one of the pro-inflammatory mediators, has been identified as a key regulator of the inflammatory response. It has attracted attention for binding to two different receptors, thereby initiating distinct signal transduction pathways. It has been found that there is a lack of relevant summaries of the different factors that make the pro-inflammatory or anti-inflammatory effects of TNF-α in TBI vary significantly. Therefore, this review examines the fundamental signaling pathways that regulate TNF-α in TBI in both the neuroimmune and inflammatory responses. It also reviews the progress of research on the pharmacological and physical technologies that target TNF-α for the treatment of TBI. The review emphasizes the biological effects of TNF-α as a receptor and ligand, as well as current difficulties and challenges.</p>