Abstract: Objective: To study the preventive effect and the related mechanisms of polysaccharide of Polygonati Rhizoma (PSP) on cognitive impairments induced by sleep interruption (SI) in mice. Methods: The 72 ICR mice were randomly divided into the control group, the SI model group, the positive control (ginkgo biloba extract) group and the PSP (100, 200, 400 mg/kg) groups. After 14 days of pretreatment, all groups except the control group received sleep interruption which lasted for 14 days. Thereafter, the behavioral tests were performed by using the open field test, the object recognition experiment, the Morris water maze task and the passive avoidance test. Following the behavioral tests, the biochemical analysis was conducted by measuring the levels of IL-1β and IL-6 in the serum and the hippocampus, the contents of GABA and Ach in the hippocampus. Results: The open field test result showed, there were no significant changes in the locomotor activities of mice among all groups (P>0.05). Compared with the SI model group, SPS (100, 200, 400 mg∙kg⁻¹) treatment markedly elevating discrimination index (DI) in object recognition experiment (P<0.05, P<0.01), decreased the error times in entering the dark chamber (P<0.05) and prolonged the latency time in passive avoidance test (P<0.05), as well as decreased the latency period of searching for stations in the navigation stage of water maze positioning (P<0.05). Moreover, PSP administration significantly decreased the levels of IL-1β and IL-6 in the serum and the hippocampus (P<0.05), the content of GABA was significantly decreased (P<0.01), while the level of Ach in the hippocampus was significantly raised (P<0.05). Conclusion: The results reveal that PSP treatment could effectively improve the cognitive impairments induced by SI and its cognition-improving effects might be related to regulate the levels of the proinflammatory cytokines and neurotransmitter in the serum and hippocampus of mice.