Traumatic brain injury (TBI) is one of the most important causes of death and disability in adults and thus an important public health problem. Following TBI, secondary pathophysiological processes develop over time and condition the development of different neurodegenerative entities. Previous studies suggest that neurobehavioral changes occurring after a single TBI are the basis for the development of Alzheimer's disease, while repetitive TBI is considered to be a contributing factor for chronic traumatic encephalopathy development. However, pathophysiological processes that determine the evolvement of a particular chronic entity are still unclear. Human post-mortem studies have found combinations of amyloid, tau, Lewi bodies, and TAR DNA-binding protein 43 (TDP-43) pathologies after both single and repetitive TBI. This review focuses on the pathological changes of TDP-43 after single and repetitive brain traumas. Numerous studies have shown that TDP-43 proteinopathy noticeably occurs after repetitive head trauma. A relatively small number of available preclinical research on single brain injury are not in complete agreement with the results from the human samples, which makes it difficult to draw specific conclusions. Also, as TBI is considered a heterogeneous type of injury, different experimental trauma models and injury intensities may cause differences in the cascade of secondary injury, which should be considered in future studies. Experimental and post-mortem studies of TDP-43 pathobiology should be carried out, preferably in the same laboratories, to determine its involvement in the development of neurodegenerative conditions after one and repetitive TBI, especially in the context of the development of new therapeutic options.