OBJECTIVE To investigate the effect of total saponin of Aralia taibaiensis (SAT) on cognitive dysfunction of mice with traumatic brain injury (TBI) by mediating silent information regulator 1 (SIRT1)/ forkhead transcription factor 1 (FoxO1)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway. METHODS C57BL/6 mice were divided into Con group, model group, SAT group (135 mg·kg^-1), EX-527 group (10 mg·kg^-1 SIRT1 inhibitor EX-527), and SAT+EX-527 group, 12 per group. Mice in the Con group received all surgical operations except cortical shock, and the controllable cortical shock method was used to construct the TBI model for the other groups. After the modeling was successful, the corresponding administration was performed, once a day for 7 d. Morris water maze test was performed to measure the learning and spatial memory abilities of mice; HE staining was performed to measure the pathological changes of damaged cortex; ELISA method was performed to measure the contents of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in damaged cortex; TUNEL staining was performed to measure neuronal apoptosis; and Western blot was performed to measure the expressions of Caspase-3, Bcl-2 related X protein (Bax), SIRT1, Ace-FoxO1, and Ace-PGC-1α proteins in damaged cortex. RESULTS Compared with the Con group, the mice in the model group had severe pathological damage to the cerebral cortex, the escape latency was extended and the number of crossing platforms was reduced, the levels of IL-6 and TNF-α, neuronal apoptosis rate, and the expressions of Caspase-3, Bax, Ace-FoxO1, and Ace-PGC-1α proteins in damaged cortex were increased, the expression of SIRT1 proteins was decreased (P<0.05). Compared with the model group, the pathological damage of the cerebral cortex of the mice in the SAT group was reduced, the escape latency was shortened and the number of crossing platforms was increased, the levels of IL-6 and TNF-α, neuronal apoptosis rate, and the expressions of Caspase-3, Bax, Ace-FoxO1, and Ace-PGC-1α proteins in damaged cortex were decreased, the expression of SIRT1 proteins was increased (P<0.05), the changes in the corresponding indicators of the EX-527 group showed an opposite trend. EX-527 reversed the improvement effect of SAT on cognitive dysfunction in TBI mice. CONCLUSION SAT may improve the cognitive dysfunction of TBI mice by activating the SIRT1/FoxO1/PGC-1α pathway.