Prolonged exposure to hyperoxia produces extraordinary amounts of reactive oxygen species (ROS) in the lung and causes hyperoxic lung injury. Although supraphysiological oxygen is routinely administered for the management of respiratory failure, there is no effective strategy to prevent hyperoxic lung injury. In our previous study, we showed that suplatast tosilate, an asthma drug that inhibits T helper 2 (Th2) cytokines, ameliorated bleomycin-induced lung injury and fibrosis through Th2-independent mechanisms. Because bleomycin also generates ROS, we hypothesized that suplatast tosilate might have antioxidant activity and protect the lung against hyperoxic lung injury. To test this hypothesis, mice exposed to hyperoxia were given suplatast tosilate through drinking water. Treatment with suplatast tosilate significantly prolonged mouse survival, reduced the increases in the numbers of inflammatory cells, levels of the pro-inflammatory cytokines/chemokines IL-6 and MCP-1, and protein in bronchoalveolar lavage fluid, and ameliorated lung injury in histological assessment. Suplatast tosilate treatment also significantly inhibited hyperoxia-induced elevations in the levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in bronchoalveolar lavage fluid and 8-isoprostane, a marker of lipid peroxidation, in lung tissue. This finding suggests that suplatast tosilate exerts an antioxidant activity in vivo. In addition, we investigated whether suplatast tosilate has a scavenging effect on hydroxyl radical, the most reactive and harmful ROS, using electron paramagnetic resonance spin-trapping. Suplatast tosilate was shown to scavenge hydroxyl radicals in a dose-dependent manner, and its reaction rate constant with hydroxyl radical was calculated as 2.6×1011 M−1 S−1, which is faster than that of several well-established antioxidants, such as ascorbate, glutathione, and cysteine. These results suggest that suplatast tosilate protects the lung against hyperoxic lung injury by decreasing the degree of oxidative stress induced by ROS, particularly by scavenging hydroxyl radicals. Suplatast tosilate might become a potential therapeutic for hyperoxic lung injury.