Prone positioning and lung-protective ventilation are key components of the management of moderate-to-severe acute respiratory distress syndrome (ARDS). However, protective ventilation may be limited by refractory hypercapnia, acidosis, and hemodynamic instability. Whether extracorporeal multiorgan support can complement prone positioning by alleviating these physiologic constraints remains unknown. Methods: We conducted a retrospective physiologic cohort study of adult patients with severe ARDS treated with prone positioning combined with extracorporeal multiorgan support using the ADVOS system. The cohort represented a highly selected population with bacterial pneumonia-associated ARDS, sepsis, acute kidney injury, and vasopressor dependence. Physiologic variables were recorded from baseline to the end of the first (t16) and second (t40) prone sessions. The primary objective was to assess short-term changes in arterial pH, PaCO₂, PaO₂/FiO₂ ratio, driving pressure, and respiratory system compliance. Results: Fifteen patients were included. Median baseline PaCO₂ was 68.1 mmHg and pH was 7.22. By t16, PaCO₂ decreased to 42.6 mmHg (p = 0.001) and pH increased to 7.41 (p = 0.001). The PaO₂/FiO₂ ratio increased from 82 to 146 (p = 0.001), and driving pressure decreased from 20 to 17 cmH₂O (p = 0.003). Mechanical power decreased from 28.5 to 25.9 J/min (p = 0.033), whereas respiratory rate and respiratory system compliance did not reach statistical significance at t16. Vasopressor requirements also decreased during the observation period. Extracorporeal support was maintained throughout prone positioning in all patients. Conclusions: In this highly selected cohort, combined prone positioning and extracorporeal multiorgan support was associated with rapid correction of hypercapnic acidosis, improved oxygenation, and favorable changes in selected measures of ventilatory load. These findings describe the integrated physiologic response to the combined strategy and warrant evaluation in prospective controlled studies.