Extubation of select neonatal and pediatric patients supported with extracorporeal membrane oxygenation (ECMO) may avoid ventilator-induced lung injury, decrease neurosedative exposure, and improve rehabilitation. A single-center retrospective cohort study was performed to describe our experience with extubation of ECMO patients in the cardiac intensive care unit (CICU), pediatric intensive care unit (PICU), and neonatal intensive care unit (NICU). This is the largest reported single-center cohort of extubated pediatric patients to our knowledge. From 2013 to 2022, we extubated 8.6% of all ECMO runs, resulting in a total of 40 patients extubated on ECMO. Extubated patients tended to be older, cannulated for pulmonary support, and tended to have longer runs. Survival to hospital discharge for extubated ECMO patients was 75%, significantly higher than the non-extubated cohort (p = 0.044). After adjustment for duration of ECMO run, extubated patients had more gastrointestinal (GI) hemorrhage and continuous renal replacement therapy (CRRT) usage, but did not have more mechanical, neurologic, cardiovascular, or pulmonary complications. With 10 years of data on extubation on ECMO, we present evidence that extubation on ECMO is feasible and can be done safely.