The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway exhibits protective effects in a variety of neurological diseases. However, the role of this pathway in traumatic brain injury (TBI) is not fully understood. This study investigates whether the Nrf2-ARE pathway provides neuroprotection following TBI via regulation of the ubiquitin proteasome system (UPS), and examines the involvement of this pathway in redox homeostasis. We found that activation the Nrf2-ARE pathway can mitigate secondary brain injury induced by TBI. Furthermore, we found that inhibiting the Nrf2-ARE pathway weakened the UPS following TBI. Treatment of TBI with the proteasome inhibitor, MG132, increased neuronal apoptosis, and evidence of brain water content was found. These data suggest that the Nrf2-ARE pathway provides neuroprotection following TBI via modulation of the UPS. In addition, the results indicated that the content of glutathione (GSH) was significantly increased after activation of Nrf2, and the level of ROS decreased; however, this effect contradictory in the Nrf2 knockout mice. Further studies found that treatment with the ROS agonist, ferric ammonium citrate (FAC), resulted in additional damage exerted by the ubiquitin proteasome pathways, and a significant increase in the amount of ubiquitinated proteins. In contrast, the activity of the ubiquitin proteasome pathways was vastly enhanced, and the level of ubiquitination proteins was significantly decreased following treatment with the inhibitor, N-acetylcysteine (NAC). The above mentioned results were also verified in in vitro experiments. In conclusion, the activation the Nrf2-ARE pathway improves neurological impairment caused by TBI via modulation of the UPS, and the redox homeostasis is one of the vital regulatory mechanisms.