Objectives: To investigate, in the model of repetitive mild traumatic brain injury (mTBI) in wild-type and TDP-43 transgenic mice, the regulation of TAR DNA binding protein 43 (TDP-43) in the frontal cortex, hippocampus, and spinal cord, then to evaluate and compare the incidence and extent of neurodegeneration and glial cells activation in the cerebrum and spinal cord, and to study motor skills, mood changes, and cognition. Material and methods: Two brain injuries were done daily for five consecutive days with the weight drop method. The levels of expression of the proteins of interest in cytoplasmic and nuclear fractions were determined by Western blotting. With immunohistochemical analyzes, the subcellular site and localization of TDP-43 in different cell types, as well as gliosis levels were examined. Fluoro-Jade C staining was used to determine the incidence and the extent of neurodegeneration. Various tests of behavior and motor functions were used. Results: In the frontal cortex of wild-type mice, translocation of TDP-43 into the cytoplasm of cells, predominantly neurons, and the overexpression of its pathological forms on the first or third day were found, while in the spinal cord increased expression of phosphorylated TDP-43 on the first day, and a decrease in TDP-43 expression in the hippocampus on the third day after the last mTBI were noticed. Six months after the injury, increased expression of TDP43 and its fragment TDP-35 were detected in the spinal cord, and a decrease in TDP-35 levels was observed in the hippocampus. Repetitive mTBI did not cause additional protein dysregulation in the studied structures and time points in TDP-43 transgenic mice. Neurodegeneration and gliosis were observed in the optic tract of animals of both genotypes, and in transgenic mice, these changes were significantly more pronounced on the seventh day after the last trauma compared to the values in wild-type animals. The motor deficit was noticed on the third post-traumatic day in mice of both genotypes, and at some chronic time points in wild-type animals. Repetitive mTBI did not affect the cognitive functions and mood of wildand TDP-43 transgenic-type mice. Conclusion: Repetitive mTBI causes different regulation of TDP-43 in individual central nervous system structures of wild-type mice, and does not affect additional protein dysregulation in transgenic animals during the first week and six months after the last injury. It also causes neurodegenerative and inflammatory changes in the optic tract, and sporadic changes in motor skills, and does not affect the cognition and mood of the animals.