This study analyzed the outcomes of neonates undergoing a second run of extracorporeal membrane oxygenation (ECMO) to determine whether there is a benefit to a repeated run. We used Extracorporeal Life Support Organization data to compare neonates undergoing a single versus two runs of ECMO from 2009 to 2019. Baseline characteristics of single-run patients were compared with the first run in two-run patients to identify clinical predictors of a second run of ECMO. Furthermore, we compared overall survival outcomes and ECMO-related complications in single-run and two-run patients, with propensity score matching to adjust for baseline differences between the groups. A total of 12,292 patients undergoing 12,668 ECMO runs met criteria. Neonates requiring a second run had a shorter duration of the first ECMO run (p < 0.001) and were more likely to have had venoarterial cannulation (p < 0.001) than single-run patients. Overall, 33.8% of patients undergoing a second run survived until discharge, compared with 62.9% of patients undergoing a single run only. Propensity score matched analysis demonstrated that patients undergoing two runs were more likely to die, irrespective of underlying physiologic status or ECMO indication (odds ratio [OR] = 3.53, 95% confidence interval [CI] = 2.75–4.56). Nevertheless, nearly a third of patients undergoing two ECMO runs survived until discharge, indicating that recannulation may be beneficial in certain patient cohorts.