Many studies have shown that spaceflight causes oxidative stress and induces brain disorder in astronauts, but the counter measurements are lacking. Increasing evidence demonstrated that hydrogen can act as a therapeutic antioxidant. In this study, rats were treated with or without about 5% hydrogen under hindlimb unloading or normal conditions for 28 d. We assessed rat’s brain function by open-field test, step-down passive avoidance test, the neurotransmitter’s level detected by liquid chromatography with tandem mass spectrometry, and Nissl and hematoxylin–eosin staining analysis. We also assessed the oxidative damage by changes of malondialdehyde level, the ratio of reduced glutathione to oxidized glutathione, and superoxide dismutase and catalase activity. Glucose metabolism disorder was disclosed through glucose metabolomic analysis. The underlying mechanism of the effects of hydrogen was analyzed by mRNA sequencing and detecting mRNA and protein levels. Our data showed that hindlimb unloading caused oxidative damage and glucose metabolism disorder in brain tissues and decreased brain function in rats. Hydrogen inhalation reduced oxidative damage, ameliorated glucose metabolism disorder, and alleviated the dysfunction of rat brain function. Peroxisome-proliferator-activated receptor gamma coactivator 1α and brain-derived neurotrophic factor, the key regulators of glucose metabolism and brain function, were obviously affected. This research confirms the protective effect of hydrogen inhalation on declining brain function under hindlimb unloading conditions and discloses the underlying mechanism, which provides a potential strategy for astronauts’ health.