Despite significant advancements in critical care practice and extracorporeal technology, refractory hypoxia remains a persistent clinical challenge during extracorporeal membrane oxygenation (ECMO). To demonstrate a systematic, algorithmic pathway for troubleshooting during ECMO support, this chapter presents a case-based approach. The presented cases explore a spectrum of etiologies, including disconnection of the oxygen source, recirculation, oxygenator malfunction, console or pump failure, cannulation-related bleeding, and hypoxia during venoarterial ECMO (VA-ECMO). Each scenario demonstrates the physiological evaluation and stepwise clinical reasoning required to identify and manage the underlying issue rapidly. Echocardiography, bedside imaging, pre and post-oxygenator blood gas analysis, and continuous circuit pressure monitoring are essential diagnostic steps. According to the report, hypoxia should not be interpreted as a single PaO₂ threshold but rather as reduced systemic oxygen delivery (DO₂) in relation to oxygen consumption (VO₂). Key management strategies involve optimizing the ECMO flow, verifying circuit integrity, correcting anemia, controlling metabolic demand, and ensuring adequate left ventricular unloading in VA-ECMO. Systematic bedside evaluation guided by physiological principles can significantly reduce morbidity and prevent catastrophic outcomes. Collectively, these case discussions underscore the importance of an algorithmic approach to managing hypoxia during ECMO, ensuring patient safety and adequate cardiopulmonary support.