Circuit thrombosis and mechanical failure are important complications during extracorporeal membrane oxygenation (ECMO), but expected circuit duration and predictors of circuit failure remain poorly defined. We performed a retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry, including patients aged less than 18 years supported with ECMO between January 2020 and December 2024. Circuit failure was defined as a mechanical complication requiring circuit or component replacement. Time to failure was analyzed using Cox proportional hazards models, and associations with mortality were analyzed using logistic regression and propensity score matching. A total of 20,124 patients with 21,294 runs and 26,318 circuits were included. Circuit failure occurred in 5,052 circuits (19.2%), with at least one replacement in 15.3% of runs. Median time to failure was 129.5 hours (interquartile range [IQR]: 55.0–262.5). Neonatal age, weight less than 3 kg, and higher center volume were associated with increased circuit failure, whereas older age was associated with lower risk. Extracorporeal membrane oxygenation pump flow was not associated with circuit failure. Circuit failure was associated with higher mortality (49.0% vs. 34.1%). In propensity score matching, circuit failure increased absolute mortality risk by 6.1 percentage points (p < 0.001), with the strongest effect in neonates. Circuit life warrants evaluation as a potential endpoint for future hemocompatibility and anticoagulation studies.