Purpose: This study aimed to evaluate the use of the respiratory rate oxygenation (ROX) index, ROX-heart rate (ROX-HR) index, and saturation of percutaneous oxygen/fraction of inspired oxygen ratio (SF ratio) to predict weaning from high-flow nasal cannula (HFNC) in patients with respiratory distress in a pediatric intensive care unit. Methods: A total of 107 children admitted to the pediatric intensive care unit were enrolled in the study between January 1, 2017, and December 31, 2021. Data on clinical and personal information, ROX index, ROX-HR index, and SF ratio were collected from nursing records. The data were analyzed using an independent t-test, χ2 test, Mann–Whitney U test, and area under the curve (AUC). Results: Seventy-five (70.1%) patients were successfully weaned from HFNC, while 32 (29.9%) failed. Considering specificity and sensitivity, the optimal cut off points for predicting treatment success and failure of HFNC oxygen therapy were 6.88 and 10.16 (ROX index), 5.23 and 8.61 (ROX-HR index), and 198.75 and 353.15 (SF ratio), respectively. The measurement of time showed that the most significant AUC was 1 hour before HFNC interruption. Conclusion: The ROX index, ROX-HR index, and SF ratio appear to be promising tools for the early prediction of treatment success or failure in patients initiated on HFNC for acute hypoxemic respiratory failure. Nurses caring for critically ill pediatric patients should closely observe and periodically check their breathing patterns. It is important to continuously monitor three indexes to ensure that ventilation assistance therapy is started at the right time.