Objective: Apoptotic cell death is an important factor influencing the prognosis after traumatic brain injury (TBI). Akt/GSK-3beta/beta-catenin signaling plays a critical role in the apoptosis of neurons in several models of neurodegeneration. The goal of this study was to determine if the mechanism of cell survival mediated by the Akt/GSK-3beta/beta-catenin pathway is involved in a rat model of TBI. Methods: TBI was performed by a controlled cortical impact device. Expression of Akt, phospho-Akt, GSK-3beta, phospho-GSK-3beta, beta-catenin, phospho-beta-catenin were examined by immunohistochemistry and Western blot analysis. Double immunofluorenscent staining was used to observe the neuronal expression of the aforementioned subtrates. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) staining was performed to identify apoptosis. Results: Western blot analysis showed that phospho-Akt significantly increased at 4 hours post-TBI, but decreased after 72 hours post-TBI. Phospho-GSK-3beta - phosphorylated by phospho-Akt - slightly increased at 4 hours post-TBI and peaked at 72 hours post-TBI. These changes in Phospho-GSK-3beta expression were accompanied by a marked increase in expression of phospho-beta-catenin at 4 hours post-TBI which was sustained until 7 days post-TBI. Double staining of phospho-Akt and NeuN revealed the colocalization of phospho-Akt positive cells and neuronal cells. In addition, double staining of phospho-Akt and TUNEL showed no colocalization of phospho-Akt cells and TUNEL-positive cells. Conclusion: Phosphorylation of Akt (Ser473) and GSK3beta (Ser9) was accelerated in the injured cortex, and involved in the neuronal survival after TBI. Moreover, neuroprotection of beta-catenin against ischemia was partly mediated by enhanced and persistent activation of the Akt/GSK3beta signaling pathway.