Abstract：Objective：To observe the effect of Sijunzi Decoction on the AMPK-SIRT1 signal pathway of exercise-induced fatigue (EF) mice， and discuss its mechanism in improving EF cognitive injury and learning and memory function. Methods：A total of 60 C57BL/6 mice were randomly divided into the blank group， the model group， the high-dose Sijunzi Decoction group， the medium-dose Sijunzi Decoction group，and the low-dose Sijunzi Decoction group. Except for the blank group，the other groups were used to establish the EF mice model with syndrome of spleen-qi deficiency. The high-dose Sijunzi Decoction group，the medium-dose Sijunzi Decoction group，and the low-dose Sijunzi Decoction group were given Sijunzi Decoction of different concentrations by gavage， and the blank group and the model group were given equal volume of distilled water by gavage. Each group was given gavage for four weeks. Morris water maze test was used to evaluate the cognitive function of mice， ELISA method was used to detect the levels of serum lactic acid，blood glucose，liver glycogen and muscle glycogen and Western Blot method was used to detect the protein expressions of AMPK and SIRT1 in brain tissue. Results：After experiment， the body mass， food intake， blood glucose， liver glycogen content， muscle glycogen content， target quadrant swimming time， number of crossing platforms， and protein expressions of AMPK and SIRT1 in the model group were lower than those in the blank group， and the level of serum lactic acid was higher than that in the blank group (P＜0.05). After intervention with drugs， the body mass， food intake， exhaustive swimming time，liver glycogen content，muscle glycogen content，target quadrant swimming time and number of crossing platform in the high-dose Sijunzi Decoction group，the medium-dose Sijunzi Decoction group， and the low-dose Sijunzi Decoction group were higher than those in the model group， and the levels of serum lactic acid were lower than those in the model group (P＜0.05). The exhaustive swimming time in the high-dose Sijunzi Decoction group was higher than that in the low-dose Sijunzi Decoction group，and the level of lactic acid was lower than that in the low-dose Sijunzi Decoction group (P＜0.05). The contents of liver glycogen and muscle glycogen in the high-dose Sijunzi Decoction group and the medium-dose Sijunzi Decoction group were higher than those in the low-dose Sijunzi Decoction group (P＜0.05). Compared with that in the model group，the protein expressions of AMPK and SIRT1 in the highdose Sijunzi Decoction and medium-dose Sijunzi Decoction group were increased (P＜0.05)， and the protein expression of SIRT1 in the low-dose Sijunzi Decoction group was increased (P＜0.05). Compared with that in the low-dose Sijunzi Decoction group，the protein expressions of AMPK and SIRT1 in the highdose Sijunzi Decoction and medium-dose Sijunzi Decoction group were increased (P＜0.05). Conclusion： Sijunzi decoction can regulate the activity of AMPK/SIRT1 to a certain extent， and further improve the symptoms of spleen deficiency in EF mice.