Background <p>High-velocity nasal insufflation (HVNI) improves oxygenation and decreases breathing effort in patients with acute hypoxemic respiratory failure (AHRF). However, evidence-based recommendations for the optimal method of transitioning from HVNI to conventional oxygen therapy are lacking. This study aimed to compare the efficacy of four distinct weaning protocols from HVNI.</p> Methods <p>This was a prospective, randomized controlled trial conducted on 120 adult patients with AHRF admitted to the Respiratory Intensive Care Unit (ICU). All patients were eligible for weaning according to European Respiratory Society criteria. Patients were randomly assigned in a 1:1:1:1 ratio to one of four groups: sudden reduction (SR), flow reduction first (FR), oxygen reduction first (OR), or simultaneous flow and oxygen reduction (FOR). The primary outcome was the rate of weaning failure. Secondary outcomes included total oxygen weaning time, length of stay, and patient outcomes.</p> Results <p>There was no statistically significant difference between the four groups in the rate of weaning failure or mortality (adjusted <i>P</i> values = 1.00 and 1.00, respectively). However, patients in the FR group had significantly shorter ICU stays (adjusted <i>P</i> = .049), shorter time from separation to discharge (adjusted <i>P</i> &lt; .001), lower SpO₂/FiO₂ ratios (adjusted <i>P</i> = .049), lower respiratory rates (adjusted <i>P</i> &lt; .001), and lower heart rates (adjusted <i>P</i> &lt; .001) one hour after separation, as well as lower oxygen demand after separation (adjusted <i>P</i> = .042).</p> Conclusion <p>Although there was no statistically significant difference in weaning failure among the four weaning methods, the flow reduction first strategy showed favourable trends in secondary outcomes, including shorter ICU stays and more favourable short-term physiological parameters.</p> Trial registration <p>ClinicalTrials.gov ID NCT06746636.</p>