Objective: Although high-flow nasal cannula (HFNC) is a commonly used treatment method to manage respiratory distress in children, it may still result in treatment failure requiring advanced airway support. Such treatment failure can lead to increased morbidity and mortality. In light of this, a cross-sectional observational study was conducted in a pediatric intensive care unit (PICU) to identify predictive factors associated with HFNC failure in children. Materials and methods: A total of 187 patients aged between one month and 18 years with moderate to severe respiratory distress treated with HFNC therapy in the PICU between October 2018 and January 2020 were included in the study. Patients with chronic lung disease and cyanotic congenital heart disease were excluded. Clinical assessments included respiratory scores, relevant laboratory data, and treatment outcomes. In the statistical analysis, data variables were evaluated using the Mann–Whitney U test, χ2 test, receiver operating characteristic, and multivariate logistic regression analysis. Results: Analysis of 114 patients revealed a HFNC treatment failure rate of 31.6%. Multivariate logistic regression revealed that the presence of medical comorbidities (OR: 25.8, 95% CI: 2.61-254.5, p=0.005), an increased mRDAI score at the first hour of HFNC therapy (OR: 2.9, 95% CI: 1.32-6.48, p=0.008), and higher PRISM scores (OR: 2.1, 95% CI: 1.44-3.07, p<0.001) were significant predictors of HFNC failure. Conclusions: This study underscores the importance of early identification of predictive factors for HFNC therapy failure to improve management strategies and patient outcomes in pediatric patients with respiratory distress.