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Onboard oxygen-generating systems (OBOGSs) provide increased inspired oxygen (F_iO₂) to mitigate the risk of neurologic injury in high altitude aviators. OBOGSs can deliver highly variable oxygen concentrations oscillating around a predetermined F_iO₂ set point, even when the aircraft cabin altitude is relatively stable. Steady-state exposure to 100% F_iO₂ evokes neurovascular vasoconstriction, diminished cerebral perfusion, and altered electroencephalographic activity. Whether non-steady-state F_iO₂ exposure leads to similar outcomes is unknown. This study characterized the physiologic responses to steady-state and non-steady-state F_iO₂ during normobaric and hypobaric environmental pressures emulating cockpit pressures within tactical aircraft. The participants received an indwelling radial arterial catheter while exposed to steady-state or non-steady-state F_iO₂ levels oscillating ± 15% of prescribed set points in a hypobaric chamber. Steady-state exposure to 21% F_iO₂ during normobaria produced arterial blood gas values within the anticipated ranges. Exposure to non-steady-state F_iO₂ led to P_aO₂ levels higher upon cessation of non-steady-state F_iO₂ than when measured during steady-state exposure. This pattern was consistent across all F_iO₂ ranges, at each barometric condition. Prefrontal cortical activation during cognitive testing was lower following exposure to non-steady-state F_iO₂ >50% and <100% during both normobaria and hypobaria of 494 mmHg. The serum analyte levels (IL-6, IP-10, MCP-1, MDC, IL-15, and VEGF-D) increased 48 h following the exposures. We found non-steady-state F_iO₂ levels >50% reduced prefrontal cortical brain activation during the cognitive challenge, consistent with an evoked pattern of neurovascular constriction and dilation.