This report presents a case series that introduces differential venous drainage (DVD) as an underrated complication arising from the hemodynamic impact of the extracorporeal life support (ECLS) circuit on a patient’s native circulation. In this series, we examine how DVD can be recognized and distinguished, particularly as its presentation may initially resemble the more extensively reported differential oxygenation (DO), a hemodynamic phenomenon observed in peripheral veno-arterial extracorporeal membrane oxygenation (V-A ECMO). Differential oxygenation, also known as differential hypoxemia or “Harlequin Syndrome,” manifests as an uneven distribution of oxygenated blood between the upper and lower body in patients on V-A ECMO. In contrast, DVD arises from DVD patterns within the circulation. Our analysis reveals cases where DVD produces symptoms similar to DO, highlighting its unique diagnostic and therapeutic challenges, its clinical significance, and its potential implications for patient outcomes. Additionally, we outline the various management strategies for both DO and DVD, underscoring the need for a deeper understanding of their respective impacts on clinical outcomes.