Hyperoxia is routinely used to prevent or treat hypoxemia and acute respiratory failure, and sustain aerobic life in military and commercial operations. However, breathing oxygen acutely at high pressures and for long durations is toxic. The present study aimed to investigate effects of hyperbaric oxygen (HBO) exposure on plasma metabolite profiles. We applied a liquid chromatography-mass spectrometry based metabolomic approach to analyze metabolites from plasma of both rats and humans under HBO conditions to explore the possible effects of HBO on the body. Uric acid (UA) and arachidonic acid concentrations were changed significantly in both rat and human plasma, and some precursor metabolites of UA in the UA pathway were also changed. For acute and chronic HBO exposures on plasma UA after exogenous UA injection, the results indicated exogenous administration of UA significantly increased plasma UA and ascorbic acid levels. However, these returned to normal levels 48 h after HBO exposure. These findings suggest HBO exposure can combat the harmful effects of increased UA from exposure to elevated partial pressure of oxygen. Furthermore, exogenous administration of UA not only does not disturb its metabolism, but also increases its anti-oxidative capacity (increase ascorbic acid). These findings suggest that the use of antioxidants might be necessary under HBO exposure, especially under extreme HBO exposure.