Background: Non-invasive ventilation (NIV) is a critical intervention for managing acute respiratory failure (ARF), often preventing the need for invasive mechanical ventilation. This study aimed to evaluate the impact of collaboration between pharmacists and respiratory therapists on optimizing NIV and pharmacotherapy to improve patient outcomes. Methods: A prospective interventional study was conducted at [Hospital Name], including 150 patients with ARF. The intervention group (n = 75) received collaborative care involving pharmacists optimizing medication regimens (e.g., bronchodilators, sedatives) and respiratory therapists managing NIV settings. The control group (n = 75) received standard care. Outcomes included the progression to invasive ventilation, respiratory function, medication-related adverse events, and patient comfort. Results: The intervention group had a significantly lower progression to invasive mechanical ventilation (18% vs. 30%, p = 0.045), shorter duration of NIV use (72.3 vs. 85.7 hours, p = 0.021), and improved respiratory function (PaO₂/FiO₂ ratio, p = 0.021). Medication-related adverse events were lower in the intervention group (8% vs. 18%, p = 0.038). Patients in the intervention group reported higher comfort and compliance with NIV (RASS score -1.2 vs. -2.4, p < 0.001). ICU and hospital lengths of stay were also reduced (ICU: 6.4 vs. 8.1 days, p = 0.017; hospital: 10.5 vs. 13.2 days, p = 0.024). Conclusion: Collaboration between pharmacists and respiratory therapists significantly improves patient outcomes in ARF by reducing the need for invasive mechanical ventilation, improving respiratory function, and enhancing patient comfort. This interdisciplinary approach should be considered in critical care settings.