Mechanical ventilation (MV) strategies in children on extracorporeal membrane oxygenation (ECMO) have not been studied much and the ventilatory parameters to avoid greater lung damage are still unclear. Our objective was to determine the relationship between conventional tidal volume (4–8 ml/kg, CTV) versus low tidal volume (<4 ml/kg, LTV) and mortality in children with MV at the beginning of ECMO. This was a retrospective cohort study that included 101 (10.9 months interquartile range [IQR]: 6.0–24.0) children. Children with LTV had greater odds of hospital mortality (adjusted odds ratio [aOR]: 2.45; 95% confidence interval [CI]: 1.05–5.71; p = 0.03) regardless of age, reason for ECMO, and disease severity, as well as a longer duration of MV after ECMO. We found no differences between the groups in other MV settings. The CTV group required fewer fibrobronchoscopies than patients with LTV (aOR: 0.38; 95% CI: 0.15–0.99; p = 0.04). We found that a tidal volume (V_T) lower than 4 ml/kg at the onset of ECMO support in children with MV was associated with higher odds of mortality, longer post-decannulation ventilation, and a greater need for fibrobronchoscopies. Lung-protective bundles in patients with ECMO and MV should consider the V_T to maintain plateau and driving pressure that avoid major lung injury caused by MV.