Objective To study the protective effect and mechanism of action of Polygonati rhizoma polysaccharide (PSP) on the cognition deficits induced by simulating an enclosed space in mice. Methods Male ICR mice (n= 72) were randomly divided into four groups: control group, model group, positive control drug treatment group (huperzine-A), and PSP treatment group (100, 200, 400 mg / kg). With the exception of the control group, all other mice were subjected to chronic restraint stress (CRS) for 35 days to establish a mouse model of cognitive impairment (restraint intensity 10 h / d, 22:00 until 8:00 the next day) and body weight monitoring was conducted. Then, behavioral tests were performed, including an open field test, object recognition experiment, Morris water maze task, and a passive avoidance method. The levels of Superoxide dismutase ( SOD) and Malondialdehyde ( MDA) in the serum and the hippocampus, and the levels of Catalase (CAT), Corticosterone (CORT), and Acetylcholine (Ach) in the hippocampus were measured. Results The open field test showed that CRS did not affect the locomotor activities of any of the groups. Compared with the control group, the discrimination index (DI) of the CRS model group in the object recognition experiment was significantly decreased (P< 0. 01, P< 0. 001), the errors times increased and the latent period decreased in the passive avoidance test (P< 0. 05), and a longer escape latency in MWM(Morris water maze)was observed in the CRS model group ( P< 0. 05). Furthermore, in the CRS model group, the SOD and CAT levels were significantly decreased, MDA was increased, and CORT and Ach were significantly increased both in the serum and hippocampus (P< 0. 05, P< 0. 001). In comparison with the CRS model group, the above indicators were markedly reversed in the PSP groups. Conclusions The result suggested that PSP treatment can improve the cognitive impairment induced by simulating an enclosed space in mice, by mechanisms that involve the amelioration of oxidative stress damage, elevation of neurotransmitter levels, and regulation of the hypothalamic-pituitary-adrenal axis.