Extended exposure to low pO2 has multiple effects on signaling cascades. Despite multiple exploratory studies, specific studies elucidating the response of lung and plasma proteome in context of surviving low pO2 exposures are lacking. In this study, we simulated low pO2(PB=40 kPa; 7620 m) exposure in male Sprague-Dawley (SD) rats for 3, 7 and 14 days. Redox stress assays and proteomics were performed using lung and plasma followed by protein network analyses. We observed that redox homeostasis was achieved after day 3 of exposure. Lung proteome revealed cytoskeletal processes were the most significant with STAT3 acting as upstream regulator. Plasma proteome revealed a focus on lipid metabolism derived inflammatory processes. Overall, during prolonged low pO2 exposure, particularly those involving slowly decreasing pressures, redox homeostasis is achieved but energy metabolism is perturbed and this leads to an immune/inflammatory signaling impetus after 3rd day of exposure. We found that an interplay of lung cytoskeletal elements, systemic energy metabolism and inflammatory proteins aid in achieving redox homeostasis and surviving extended low pO2 exposures. Qualitative perturbations to cytoskeletal stability and innate immunity/inflammation were also observed during extended low pO2 exposure in humans exposed to 14,000 ft for 7, 14 and 21 days.