Abstract: To explore the ameliorative effect of Acanathopanax senticosus polysaccharides (ASPs) on depressive behavior and possible mechanism, Wistar rats were divided into normal control group, model control group, fluoxetine hydrochloride group (2.1 mg/kg) and low-dose and high-dose ASPs groups (60 and 120 mg/kg, n=10). The depression model was established by solitary confinement and chronic mild unknown stress stimulation for 28 d, and the rats were given intragastric administration on the first day of modeling. Depressive behaviors were evaluated by open box experiment, sugar water preference experiment and forced swimming experiment. Hematoxylin-eosin staining and Nissl staining were used to detect hippocampal histopathology, and the indexes changes of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), phosphorylated phosphatidylinositol 3 kinases (p-PI3K), phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) in each group were compared. The results proved that compared with normal control group, the number of horizontal activities and sugar water preference of model control group were significantly decreased (P<0.01), and the immobile swimming time was significantly increased (P<0.01), and the pathological changes of hippocampal tissue were obvious; compared with model control group, the number of horizontal activities and sugar water preference of low-dose and high-dose ASPs groups were significantly increased (P<0.01), and the immobile swimming time was decreased (P<0.05, P<0.01), and the pathological changes of hippocampal structure were improved. Meanwhile, compared with normal control group, the levels of IL-1β, IL-6, TNF-α and MDA in model control group were significantly increased (P<0.01), while the activities of CAT and SOD and the protein expressions of p-PI3K, p-Akt and p-mTOR were significantly decreased (P<0.01); compared with model control group, the levels of IL-1β, IL-6, TNF-α and MDA were decreased (P<0.05, P<0.01), and the activities of CAT and SOD and the protein expressions of p-PI3K, p-Akt and p-mTOR were increased (P<0.05, P<0.01) in low-dose and high-dose ASPs groups. These results suggest that ASPs can ameliorative depressive behavior in depression model rats, and its mechanism is related to the regulation of PI3K/Akt/mTOR pathway and the anti-inflammatory and antioxidant stress effects.