Background: Treatment for acute hypoxemic respiratory failure (AHRF) includes treating the underlying disease, conventional oxygen therapy (COT), noninvasive ventilation (NIV), high-flow nasal oxygen (HFNO), and invasive mechanical ventilation. Aim: The aim of this study was to compare the use of HFNO and NIV in patients with moderate-to-severe AHRF to the tertiary level intensive care unit (ICU) of a teaching hospital. Methods: All adult patients admitted to the ICU with AHRF and failed COT were included. Administration of HFNO or NIV was protocol-based and targeted improvement in oxygen saturation, respiratory rate, PaO₂, and PaCO₂. Demographic data, clinical details, vital parameters, and laboratory findings were noted at prespecified intervals. Acute Physiology and Chronic Health Evaluation II at 24 h of ICU admission and daily Sequential Organ Failure Assessment were noted. The primary outcome was failure of treatment modalities defined as need for intubation and invasive ventilation. The secondary outcomes measured at 28 days were differences in ventilator-free days, ICU and hospital length of stay, patient comfort, and mortality. Results: A total of 35 patients were included in the study. Treatment failure was 20.8% (5/24) in the NIV group and 36% (4/11) in the HFNO group (P = 0.32). The number of ventilator-free days at day 28 was 22.67 ± 9.92 and 19.36 ± 12.45 (P = 0.44) in the NIV and HFNO groups, respectively. Mortality at 28 days was 12.5% (3/24) and 27.2% (3/11) in the NIV and HFNO groups, respectively (P = 0.282). Conclusion: Treatment with HFNO is associated with nonsignificant increase in the need for intubation and 28-day mortality compared to NIV. Larger studies are required to assess the utility of HFNO in moderate-to-severe AHRF.