Hypoxia is the reduction of alveolar partial pressure of oxygen (PAO2). Military members and people who practice recreational activities from moderate to high altitudes are at risk for hypoxic exposure. Hypoxemia's signs and symptoms vary from asymptomatic to severe responses, such as excessive hypoxic ventilatory responses and residual neurobehavioral impairment. Therefore, it is essential to identify hypoxia-induced biomarkers to indicate people with exposure to hypoxia. Advances have been made in understanding physiologic responses to hypoxia, including elevations in circulating levels of endothelin 1 (ET-1) and micro RNA 21 (miR-21) and reduction in circulating levels of hydrogen sulfide (H2S). Although the levels of these factors change upon exposure to hypoxia, it is unclear if these changes are sustained upon return to normoxia. We hypothesize that hypoxia-induced ET-1 and miR-21 remain elevated, while hypoxia-reduction in H2S sustains after returning to normoxic conditions. To test this hypothesis, we exposed male rats to 6 hours of 12% O2 and measured circulating levels of ET-1 and miR-21, pre, during, and post hypoxia. We found that ET-1 plasma levels increased in response to hypoxia but returned to normal levels within 30 minutes following the restoration of normoxia. miR-21 plasma levels and transdermal H2S emissions decreased in response to hypoxia, remaining decreased upon return to normoxia, thus following the biomarker criteria. Therefore, this study supports a unique role for plasma miR21 and transdermal H2S as hypoxia biomarkers that could be used to identify individuals after exposure to hypoxia.