Background: About 10 million individuals suffer from traumatic brain injury (TBI) each year in the world, which is one of the most serious neurological disorders. The morbidity of TBI is 55.5~6.1/100,000 in China, which takes more costing in the therapy, and the outcome of that is not well. Therefore, we expect to find new methods to treat TBI and improve the outcomes of TBI. In the previous studies reviewed, we found that stem cell transplantation may hold promising potential for modifying motor dysfunction induced by TBI. Methods: Twenty-six adult SD rats were involved in our study. Two adult SD rats were used as donors of bone marrow stem cells (BMSCs), and the other adult SD rats were divided into four groups randomly, which were used to establish the TBI models. BMSCs were transduced with lentivirous-Sox2, and we try to examine the effects of Sox2 on the differentiation of BMSCs. Establishment of rat TBI model: Rats were anesthetized using pentobarbital sodium (at a concentration of 1.5% and a dose of 40 mg/kg) and fixed under the stereotaxic device. A 1.0-cm craniotomy was performed lateral to the sagittal suture. The skullcap was carefully removed, and rats were then subjected to TBI using a controlled cortical injury instrument. A standardized parietal contusion was performed using a 20-mg steel rod with a diameter of 4 mm, which dropped from a height of 30 cm. After injury, the incision was sutured, and rats were carefully observed and nursed. Treatments: Seven days after TBI, rats were divided into four groups and were transplanted with BMSC-Sox2, single BMSC, single Lentivirus-Sox2, and PBS into injured brain, respectively. The motor function was tested using the neurological severity score (NSS). Results: We found that the ectopic expression of Sox2 enhanced BMSCs to differentiate into neurons. Seven days after TBI, the rats were treated with BMSC-Sox2, BMSC, Sox2, and PBS. Results showed that NSS were 3.352 ± 0.398 in the BMSC-Sox2 group, 4.013 ± 0.495 in the BMSC group, 4.968 ± 0.293 in the Sox2 group, and 6.257 ± 0.361 in the PBS group, suggesting that there were obvious improvements in the neurological function in BMSC-Sox2, BMSC, and Sox2 groups. In addition, the BMSC-Sox2 group had the lowest scores, p < 0.05. Conclusion: The ectopic expression of Sox2 could enhance BMSCs to differentiate into neurons, and intervention of BMSCs combined with Sox2 transplantation could promote recovery of motor function in rats with TBI. © 2019 The Author(s).