Abstract Purpose This study aimed to investigate air leakage during invasive mechanical ventilation (IMV) in a pediatric intensive care unit (PICU) and explore potential risk factors. Methods We conducted a retrospective cohort study of children who underwent IMV in a single-center PICU in a tertiary referral hospital. Air leakage risk factors and factors associated with an improved outcome were assessed. Results A total of 548 children who underwent IMV were enrolled in this study. Air leakage occurred in 7.5% (41/548) of the cases in the PICU. Air leakage increased the duration of IMV and hospitalization time. Multivariate logistic regression analysis showed a higher risk of air leakage during IMV for PICU patients with acute respiratory dyspnea syndrome (ARDS) (OR = 4.38), a higher pediatric critical illness score (PCIS) (OR = 1.08), or a higher peak inspiratory pressure (PIP) (OR = 1.08), whereas the risk was lower for patients with central respiratory failure (OR = 0.14). The logistic model had excellent predictive power for air leakage, with an area under the curve of 0.883 and tenfold cross-validation. Patients aged between 1 and 6 years who were diagnosed with measles or pneumonia and had a low positive end-expiratory pressure (PEEP) or high PaO₂/FiO₂ ratio were associated with improved outcomes. Patients diagnosed with central respiratory failure or congenital heart diseases were associated with less desirable outcomes. Conclusions Patients with ARDS, a higher PCIS at admission or a higher PIP were at higher risk of air leakage.