Extracorporeal life support (ECLS) is a treatment for acute respiratory failure that can provide extracorporeal gas exchange, allowing lung rest. However, while most patients remain mechanically ventilated during ECLS, there is a paucity of evidence to guide the choice of ventilator settings. We studied the associations between ventilator settings 24 hours after ECLS initiation and mortality in pediatric patients using a retrospective analysis of data from the Extracorporeal Life Support Organization Registry. 3497 patients, 29 days to 18 years of age, treated with ECLS for respiratory failure between 2015 and 2021, were included for analysis. 93.3% of patients on ECLS were ventilated with conventional mechanical ventilation. Common settings included positive end-expiratory pressure (PEEP) of 10 cm H2O (45.7%), delta pressure (ΔP) of 10 cm H2O (28.3%), rate of 10–14 breaths per minute (55.9%), and fraction of inspired oxygen (FiO2) of 0.31–0.4 (30.3%). In a multivariate model, PEEP >10 cm H2O (versus PEEP < 8 cm H2O, odds ratio [OR]: 1.53, 95% CI: 1.20–1.96) and FiO2 ≥0.45 (versus FiO2 < 0.4; 0.45 ≤ FiO2 < 0.6, OR: 1.31, 95% CI: 1.03–1.67 and FiO2 ≥ 0.6, OR: 2.30; 95% CI: 1.81–2.93) were associated with higher odds of mortality. In a secondary analysis of survivors, PEEP 8–10 cm H2O was associated with shorter ECLS run times (versus PEEP < 8 cm H2O, coefficient: −1.64, 95% CI: −3.17 to −0.11), as was ΔP >16 cm H2O (versus ΔP < 10 cm H2O, coefficient: −2.72, 95% CI: −4.30 to −1.15). Our results identified several categories of ventilator settings as associated with mortality or ECLS run-time. Further studies are necessary to understand whether these results represent a causal relationship.