Background <p>Hypoxia remains a concern for aircrew operating high performance aircraft. Sensing and mitigating hypoxia is a line of active research within the US Air Force and US Navy. It is hypothesized that changes in exhaled breath volatile organic compound content could indicate, not only changes in oxygen saturation (SpO₂), but also brain activity and cognitive function.</p> Methods <p>On-line exhaled breath monitoring via proton transfer reaction mass spectrometry was used to observe changes in volatile organic compound concentrations during mask-free hypoxic exposures. Additionally, electroencephalography measurements in response to an odd-ball paradigm and cognitive tasks were collected throughout the exposures.</p> Results <p>The data show hypoxic exposures induced a physiological response including a significant reduction in SpO₂, a decrease in the electroencephalography waveform peak-to-peak amplitude (<i>p</i> &lt; 0.05), a significant increase in psychomotor vigilance test response time, and an increase in perceived symptomatology. Exhaled breath results indicate 19 volatile organic compound features are significantly different between hypoxia and normoxia (<i>p</i> &lt; 0.05) with 13 showing an increase in exhaled breath compared to background measurements (<i>p</i> &lt; 0.05). Linear mixed modeling with stepwise reduction demonstrates 7 of the features are significantly indicative of changes in SpO₂ with 3 and 4 features indicative of changes in brain wave functions and psychomotor vigilance test response times, respectively.</p> Conclusions <p>The data establish, for the first time, differences in exhaled breath volatile concentrations that indicate changes in cognition derived from hypoxic insult.</p>