Hypobaric hypoxia (HH) at high altitudes leads to a wide range of cognitive impairments which can handicap human normal activities and performances. However, the underlying mechanism is still unclear. Adenosine A receptors (ARs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of AR regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether AR-mediate neuroinflammation involves in cognitive impairments under acute HH. AR knock-out and wild-type male mice were exposed to a simulated altitude of 8000 m for 7 consecutive days in a hypobaric chamber and simultaneously received behavioral tests including Morris water maze test and open filed test. AR expression, the activation of microglia and the production of TNF-α were evaluated in the hippocampus by immunohistochemistry and ELISA, respectively. Behavioral tests showed that acute HH exposure caused the dysfunction of spatial memory and mood, while genetic inactivation of AR attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that ARs were mainly expressed on microglia and up-regulated in the hippocampus of acute HH model mice. Acute HH also induced the accumulation of microglia and increased production of TNF-α in the hippocampus, which could be markedly inhibited by AR inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by AR activation involves in acute HH-induced spatial memory impairment and that AR could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes.