Initial studies have found some evidence for transactive response DNA-binding protein 43 (TDP-43) abnormalities after traumatic brain injury (TBI), and the presence of protein inclusions consisting of TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis (ALS), a condition associated with TBI. However, no study has characterized changes in TDP-43 phosphorylation, mislocalization, and fragmentation (i.e., abnormalities linked to hallmark TDP-43 pathology) after TBI, and how these relate to functional outcomes. Further, how TBI affects an individual with a known predisposition to TDP-43 pathology is unknown. Therefore, this study examined the effects of TBI on TDP-43 post-translational processing, localization, and behavioral outcomes in wild-type (WT) mice and mutant TDP-43A315T mice (i.e., mice predisposed to TDP-43 pathology) at 24 h and 1 week after TBI. Post-mortem brain tissue from human patients with acute TBI was also examined. Western blots found that WT mice given TBI had increased TDP-43 phosphorylation, mislocalization, and fragmentation compared with sham-injured WT mice. The TDP-43A315T mice given a TBI had exacerbated TDP-43 abnormalities, worse cell death, and cognitive deficits compared with all other groups. In the human TBI patients, the only significant finding was increased nuclear accumulation of phosphorylated TDP-43 fragments. The discrepancy between the robust mouse findings and the largely non-significant human findings may be due to factors including heterogeneity in clinical TBI, the small group sizes, and temporal complexities with TDP-43 abnormalities. These findings indicate that TBI can induce a number of TDP-43 abnormalities that may contribute to the neurological consequences of TBI, though further research is still needed.