Background: The PaO2/FiO2 (PF) ratio derived from arterial blood gas analysis is the reference standard for grading oxygenation in critically ill children, but repeated arterial sampling is invasive and frequently impractical in the pediatric intensive care unit (PICU). The SpO2/FiO2 (SF) ratio obtained from pulse oximetry offers a non-invasive, continuous alternative. Aim: To compare the SF and PF ratios and evaluate the SF ratio as a surrogate marker of oxygenation, disease severity and outcome in critically ill children requiring respiratory support. Methods: This prospective observational study enrolled 125 children aged 2 months to 16 years requiring respiratory support (invasive ventilation, non-invasive ventilation or high-flow nasal cannula) in the PICU of a tertiary care hospital over 24 months. SpO2, PaO2 and FiO2 were recorded simultaneously at admission and again at clinical deterioration or 24 hours, whichever was earlier. SF and PF ratios were calculated and compared across ARDS severity, respiratory support modality and clinical outcome. Analysis was performed in SPSS v29.0; p < 0.05 was significant. Results: Mean age was 4.6 ± 4.4 years; bronchiolitis (23.2%) and pneumonia (12.0%) were the commonest diagnoses. SF and PF ratios fell in parallel with increasing ARDS severity at admission (non-ARDS SF 319.1/PF 393.1 vs severe SF 193.9/PF 209.5; p < 0.001 for both) and at 24 hours (p < 0.001). Both ratios were lowest in mechanically ventilated children and in non-survivors (admission SF 203.7/PF 202.0 in those who died vs SF 255.2/PF 276.5 in those discharged; p = 0.013 and 0.008). The prognostic separation widened at 24 hours (PF p < 0.001). Conclusion: The SF ratio paralleled the PF ratio across severity, support modality and outcome, supporting its use as a reliable non-invasive surrogate that may reduce arterial sampling and aid early risk stratification in the PICU.