In aerospace medicine, the influence of microgravity on cognition has always been a risk factor threatening astronauts’ health. The traditional medicinal plant and food materialGastrodia elataBlume has been used as a therapeutic drug for neurological diseases for a long time due to its unique neuroprotective effect. To study the effect of freshGastrodia elataBlume (FG) on cognitive impairment caused by microgravity, hindlimb unloading (HU) was used to stimulate weightlessness in mice. The freshGastrodia elataBlume (0.5 g/kg or 1.0 g/kg) was intragastrically administered daily to mice exposed to HU and behavioral tests were conducted after four weeks to detect the cognitive status of animals. The behavioral tests results showed that freshGastrodia elataBlume therapy significantly improved the performance of mice in the object location recognition test, Step-Down test, and Morris Water Maze test, including short-term and long-term spatial memory. According to the biochemical test results, freshGastrodia elataBlume administration not only reduced serum factor levels of oxidative stress but also maintained the balance of pro-inflammatory and anti-inflammatory factors in the hippocampus, reversing the abnormal increase of NLRP3 and NF-κB. The apoptosis-related proteins were downregulated which may be related to the activation of the PI3K/AKT/mTOR pathway by freshGastrodia elataBlume therapy, and the abnormal changes of synapse-related protein and glutamate neurotransmitter were corrected. These results identify the improvement effect of freshGastrodia elataBlume as a new application form ofGastrodia elataBlume on cognitive impairment caused by simulated weightlessness and advance our understanding of the mechanism of freshGastrodia elataBlume on the neuroprotective effect.