Objectives: To determine the incidence and extent of TDP-43 expression of the ipsilateral and contralateral cortex and hippocampus after a single moderate traumatic brain injury (TBI), compare TDP-43 subcellular localization after single moderate TBI and repetitive mild traumatic brain injury (rmTBI), and determine the association of TDP-43 expression with markers of synaptogenesis and inflammation after TBI. Material and methods: Lateral fluid percussion injury (LFPI) was used to induce the single moderate TBI, while the weight drop method was used to cause the rmTBI. The levels of expression of proteins of interest were analyzed in the cytoplasmic and nuclear fractions of the ipsilateral and contralateral cortex and hippocampus in the animals of the LFPI and in the frontal cortex and the hippocampi of rmTBI mice. Histological techniques were used to determine brain changes, and immunofluorescent techniques were used to monitor the subcellular localization of TDP-43 and its association with some markers of inflammation and synaptogenesis. Results: The ipsilateral cortex of the LFPI group is the most damaged brain structure accompanied by white matter disintegration. Also, a translocation of TDP-43 into the cytoplasm was detected on the first and third day after LFPI in the neurons and microglia of the ipsilateral cortex. In the ipsilateral hippocampus, a decrease in the expression of nuclear TDP-43 was found on the third day after one moderate TBI. Fourteen days after LFPI and rmTBI, an increase in nuclear TDP-43 expression was observed in the ipsilateral and frontal cortex, respectively. Significant increases in the expression of TDP-35, P-TDP-43 and P-TDP-35 were detected subacutely only in the ipsilateral hippocampus of the LFPI animals. The association with inflammation marker NF-κB and TDP-43 was found around the area of the greatest cortical damage. Also, significant iNOS expression with the interconnection with TDP-43 was evident in the ipsilateral cortex on the first day after LFPI. The decline in PSD-95 expression with loss of ipsilateral cortical neurons was followed by a positive correlation with TDP-43 on the first, third and fourteenth day after LFPI. An increase in APP protein expression was observed subacutely only in the rmTBI group of animals, and P-tau protein only in the LFPI mice. Conclusion: One moderate LFPI causes deregulation of TDP-43 in the ipsilateral cortex and hippocampus and it is related to some markers of inflammation and synaptogenesis. These changes depend on the type of the acquired brain trauma and are of potential importance in TBI pharmacotherapy.