The primary objective of this study was to evaluate whether pediatric respiratory rate-oxygenation index (p-ROXI) and variation in p-ROXI (p-ROXV) can serve as objective markers in children with high-flow nasal cannula (HFNC) failure. In this prospective, single-center observational study, all patients who received HFNC therapy in the general pediatrics ward, pediatric intensive care unit, and the pediatric emergency department were included. High-flow nasal cannula success was achieved for 116 (88.5%) patients. At 24 h, if both p-ROXI and p-ROXV values were above the cutoff point (>= 66.7 and >= 24.0, respectively), HFNC failure was 1.9% and 40.6% if both were below their values (p < 0.001). At 48 h of HFNC initiation, if both p-ROXI and p-ROXV values were above the cutoff point (>= 65.1 and >= 24.6, respectively), HFNC failure was 0.0%; if both were below these values, HFNC failure was 100% (p < 0.001).