Objective: This study aimed to identify and evaluate clinical predictors of High Flow Nasal Canulla (HFNC) failure in pediatric patients with acute respiratory failure (ARF). Methods: We conducted a prospective observational cohort study involving 107 children aged 28 days to 14 years admitted to the Pediatric Units of a tertiary hospital. Patients with ARF who received HFNC as respiratory support were included. Clinical and respiratory parameters were monitored at multiple time points. Results: 97 patients were eligible for analysis. The cohort consisted of 76 successes (78.4%) and 21 failures (21.6%). Within the first hour of therapy, a heart rate exceeding 167.5 beats per minute demonstrated particularly high specificity (93.4%) for subsequent failure. By the second hour, two indicators became apparent: a respiratory rate above 47.5 breaths per minute (AUC 0.67, 95% CI 0.58-0.76) and a Respiratory Rate-Oxygenation (ROX) index below 5.8, the latter showing excellent negative predictive value (92%) that could reassure clinicians about continued HFNC suitability. The most powerful predictor emerged at the 6-hour mark, where a ROX index below 4.8 achieved the highest discriminative capacity (AUC 0.73, 95% CI 0.65-0.81) with 91% sensitivity, while the flow-corrected S/F/RRSD ratio below 136 provided complementary specificity (82%). Conclusion: This study suggests that early, safe, and effective prediction of HFNC failure in pediatric ARF is achievable, potentially optimizing clinical decision-making. The ROX index (particularly at 6 hours) was the strongest predictor, showing the highest accuracy, sensitivity, and specificity, followed by measurements at 2 and 12 hours.