High-flow nasal cannula (HFNC) therapy has emerged as an important method of respiratory support in the pediatric emergency department (ED), but its optimal use and factors affecting success require further investigation. The aim of this study was to evaluate the diagnosis and treatment response of patients receiving HFNC therapy in the pediatric ED and to investigate the factors affecting the success of HFNC therapy. This retrospective, cross-sectional study analyzed the data of 415 patients admitted to the Pediatric ED of the Istanbul Medical Faculty from 2021 to 2022 who received HFNC therapy. Treatment failure was defined as the required noninvasive ventilation (NIV) or intubation. Diagnoses were confirmed by examination findings, radiological imaging, laboratory tests and other hospital admissions. Respiratory disease was diagnosed in 88.2% of patients. The most common diagnoses were bronchiolitis (48%), pneumonia (23.6%), asthma (9.6%), reactive airway disease (5.8%), and heart failure (4.8%). Among the patients, 55.4% were admitted to the pediatric service, 28% were admitted to the intensive care unit, 8.7% were discharged, and 7.7% left the ED with a referral to an external center. HFNC therapy ended with symptom regression in 63.9% of patients, transition to NIV in 25.8%, and intubation in 4.3%. Although patients did not respond to HFNC therapy at 0 to 1 hour, a HFNC response was observed in almost half of the patients in the following periods. The presence of chronic disease and abnormal chest radiography findings were found to be independent risk factors for treatment failure, whereas the presence of allergic disease and the duration of HFNC therapy were found to be protective factors. HFNC therapy was effective in most pediatric patients with respiratory distress. Clinicians should consider extending HFNC therapy beyond the first hour in initial nonresponders, as significant improvement may occur in the following hours. Chronic disease and abnormal chest radiography findings were independent risk factors for failure of HFNC therapy. Conversely, allergic disease and longer HFNC duration were protective. Clinical and laboratory parameters should be considered when evaluating the efficacy of HFNC therapy. Therefore, patients should be evaluated individually, and treatment should be planned.