Objective: With China's manned spaceflight project entering the medium and long-term flight stage, the weightless environment faced by astronauts during their long-term stay in space has become an important challenge affecting their cognitive function. The purpose of this study is to systematically explore the influence of weightlessness environment on learning and memory ability of mice and its potential molecular mechanism by establishing a simulated space weightlessness model on the ground. Methods: Male ICR mice were used to establish a simulated space weightlessness model by 30 tail suspension method, and the intervention lasted for 4 weeks. The changes of learning and memory ability of mice were evaluated by a series of behavioral tests, such as Y maze, new object recognition, Morris water maze, platform jumping and shuttle experiment. The contents of H2O2 and MDA in SirT1 of mice were detected by ELISA, and the oxidative stress （Nrf2/HO-1 pathway）, inflammation （IL-33, COX-2）, apoptosis （Caspase-3, Caspase-8, bcl-2/bax） and mitochondrial function （mtTFA, P-mTOR/mTOR） in hippocampus were detected by Western blot. Results: Compared with the blank control group, after 4 weeks of simulated weightlessness, the discrimination index of mice in the new object recognition experiment was significantly reduced （P<0.05）, the latency of seeking platform in the water maze experiment was significantly prolonged （P<0.05~0.001）, the time of safe zone in the platform jumping experiment was significantly reduced （P<0.001）, and the number of active shuttles in the shuttle experiment was significantly reduced （P < 0.05）. The contents of H2O2 and MDA in the brain tissue of simulated weightlessness mice increased significantly （P<0.05）. The relative expression of Nrf2 and HO-1 protein in hippocampus of simulated weightlessness mice was significantly decreased （P < 0.05 ~ 0.001）. The relative expression of inflammatory related proteins IL-33 and COX-2 increased significantly （P < 0.05-0.01）. The relative expression of pro-apoptosis related proteins Bax, Caspase-3 and Caspase-8 increased significantly （P < 0.01）. The relative expression of anti-apoptosis protein Bcl2-2 decreased significantly （P < 0.01）. The relative expression levels of mitochondrial function-related proteins mtTFA, P-mTOR/mTOR, SirT1 and SirT3 decreased significantly （P<0.05~0.001）. Conclusion: Simulated weightlessness in space can lead to a significant decline in learning and memory ability of mice, and its mechanism may be related to multiple pathophysiological processes such as increased oxidative stress, activation of inflammatory response, increased apoptosis and mitochondrial dysfunction in hippocampus. This study provides an experimental basis for deeply understanding the pathogenesis of cognitive dysfunction in space weightlessness environment, and also lays a theoretical foundation for developing targeted protective measures.