Extracorporeal membrane oxygenation (ECMO) is a last resort treatment for children with cardio-respiratory failure. Some of these patients will develop thrombocytopenia-associated multiple organ failure (TAMOF), which is sometimes managed with therapeutic plasma exchange (TPE). Our objective is to describe critically ill children on ECMO who underwent TPE for TAMOF. We conducted a single-center retrospective case series of seven children with congenital cardiac disease, requiring ECMO, diagnosed with TAMOF, and treated with TPE between 12/2023 and 6/2024. A centrifugation-based apheresis instrument was used to process 1.5 total blood volume. One packed red blood cell was used to prime the apheresis circuit. Systemic bivalirudin was used for anticoagulation. Seven patients (median age: 55 days, median weight: 4.0 kg, median bypass time: 172 min, 100% VA ECMO, 85% central cannulation, 100% bivalirudin) underwent a total of 30 TPE sessions. The median number of sessions per patient was 3, with a median time to first session of 27.3 h after cannulation. Plasma was used as the replacement fluid in all sessions, with a median volume of 168 mL/kg. The median platelet count increased from 45 × 10⁹/L (38; 54) pre-TPE to 64 (IQR: 45; 75, p < 0.001) post-TPE, despite no platelet transfusions during TPE. The modified organ severity index decreased significantly from 13 to 12 (p < 0.001). The mortality rate was 71%. TPE may improve platelet counts and reduce organ severity scores in critically ill children with TAMOF on ECMO.