Despite high mortality rates, pediatric extracorporeal membrane oxygenation (ECMO) redeployments are frequently discussed in everyday clinical care. We aim to investigate predictors of mortality in those patients. Clinical data from a single pediatric center were retrospectively analyzed. Patients with multiple ECMO runs between 2010 and 2023 were included. A total of 70 (13%) patients required multiple ECMO runs. Of those, 56 (80%) died before discharge; late mortality was 89% at a median of 1.6 (1.0–3.9) years. A total of 47 (67%) patients had neurologic findings. Only one (1%) survivor had a normal neurodevelopmental follow-up. Duration of the first ECMO run (odds ratio [OR]: 2.63, 1.08–7.96), total duration on ECMO (OR: 4.72, 1.29–23.54), neurologic findings at any time (OR: 7.94, 1.46–43.24), need for renal replacement therapy (OR: 4.79, 1.06–25.58), and lactate values correlated with late mortality. All 19 (27%) patients with neurologic findings before the second run died. The frequency of multiple-run ECMOs increased within the study period. Outcomes in pediatric patients with multiple ECMO runs are disheartening. Given all patients in our cohort with neurological findings before the second ECMO run died, neurological findings should be taken into consideration when determining the utility of further ECMO support.