During the long-term orbital flight, exposure to microgravity negatively affects the astronauts’ development of cognition, characterized by learning and memory decline. Gastrodia elata Blume (GEB) has a significant protective effect on cognitive impairment and has been used in Asia for centuries as a functional product. A previous study demonstrated that GEB could improve memory loss in mice caused by circadian rhythm disorders. However, the effects of GEB on cognitive dysfunction caused by weightless environments have not been investigated. In this study, mice received daily treatment with GEB (0.5, 1 g·kgd, i.g) and Huperzine A(Hup, 0.1 mg·kgd, i.g) orally until the end of the behavioral test (New object recognition test (NORT). Malondialdehyde (MDA) and nitric oxide (NO) levels were detected by kits, and expression of brain-derived neurotrophic factor (BDNF), protein kinase B (AKT), phosphorylated Akt (P-AKT), synaptophysin (SYN) and postsynaptic density 95(PSD95) in hippocampus were detected by western blotting. The results show that administration of GEB (0.5, 1 g·kgd, i.g) and Hup (0.1 mg·kgd, i.g) remarkably reverse HLS-induced learning and behavioral memory disorders, which were associated with significant changes in MDA and NO levels. Additionally, the protein expressions of BDNF, P-AKT/AKT, SYN, and PSD95 were significantly increased in the hippocampus. In summary, our findings will improve the reference for developing GEB as a functional product that improves memory decline.Copyright © 2022. Published by Elsevier B.V.