Background: Extubation failure is known as the failure to sustain sufficient spontaneous breathing following the removal of an artificial airway, particularly in high-risk patients. This condition poses a significant risk of complications during and after reintubation. Non-invasive Positive pressure ventilation (NIV) and high-flow nasal cannula (HFNC) are used as successful strategies for reducing these risks. However, further research is needed to evaluate their effectiveness and conduct direct outcome comparisons. Objective: This trial aimed to examine how non-invasive ventilation (NIV) and high-flow nasal cannula (HFNC) influence the necessity of reintubation for patients who are very likely to fail extubation. Patients and methods: This prospective randomized controlled trial (RCT) enrolled 120 critically ill adult patients in the ICU who were at elevated risk of extubation failure. All participants had undergone invasive mechanical ventilation for a minimum of 24 hours and were deemed prepared for extubation post passing a spontaneous breathing trial (SBT). Following extubation, subjects were assigned randomly into 2 equal groups: One receiving non-invasive ventilation (NIV) and the other high-flow nasal cannula (HFNC) therapy. Results: Of all the patients, 70 males were involved, the median age of the participants was 60 years (IQR: 55–63). No significant differences were detected among groups concerning baseline characteristics such as age, sex, BMI, APACHE II scores, or the presence of comorbid conditions. Clinical outcomes showed comparable effectiveness between respiratory support modalities. Reintubation was avoided in 75% of patients receiving non-invasive ventilation versus 78.3% of those using high-flow nasal cannula (p=0.672). Infectious complications occurred at similar frequencies, with ventilator-associated pneumonia rates of 15% and 16.7% (p=0.80), and sepsis incidence of 21.7% versus 26.7% (p=0.52) for non-invasive ventilation and high-flow nasal cannula respectively. However, treatment tolerance differed substantially, with non-invasive ventilation showing a significantly higher rate of device intolerance (15% vs 3.3%, p=0.02). Conclusions: HFNC may be at least as effective as NIV in reducing the risk of reintubation in patients with likelihood of extubation failure. Additionally, HFNC oxygen therapy was linked to fewer adverse effects and was better tolerated.