High altitude (HA) exposure disrupts the efficiency of the antioxidant system and can lead to oxidative damage in various organs and tissues. The present study investigated the effect of hyperoxygenated solution (HOS) intravenous infusion therapy on oxidative damage induced by acute hypobaric hypoxia. Experimental rabbits were exposed to a simulated high altitude (HA), equivalent to 8500 m, in an animal decompression chamber for 3 h. HOS infusion attenuated the rise in malondialdehyde (MDA) levels and the decrease of the reduced oxidized glutathione (GSH/GSSG) ratio. HOS also increased the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); the arterial partial pressure of oxygen (Pao(2)); and arterial blood oxygen saturation (Sao(2)) levels. Animals treated with HOS had higher Pao(2) compared with those subjected to airway oxygen therapy (p < 0.01) during HA exposure. These observations suggest that HOS intravenous infusion exerts protective effects against acute hypobaric hypoxia-induced oxidative damage.