Background <p>Mechanical ventilation is a critical life support for ICU patients. However, this intervention can be associated with complications such as patient-ventilator asynchrony (PVA) and subsequent adverse events. This study aimed to investigate the impact of implementing a PVA management protocol on clinical outcomes in ICU patients.</p> Methods <p>In this single-blind randomized controlled trial conducted from January to August 2024, a total of 66 mechanically ventilated patients admitted to the ICU of a hospital affiliated with Ahvaz Jundishapur University of Medical Sciences (Ahvaz, Iran) were randomly allocated to either an intervention or control group using a permuted block randomization method. Patients in the intervention group were evaluated for patient–ventilator asynchrony (PVA) every two hours throughout their ICU stay, as long as they remained on mechanical ventilation. If PVA was detected, appropriate interventions were implemented in accordance with the protocol of PVA management. The control group received routine care without a specific PVA management protocol. Data were collected using a structured checklist and analyzed using SPSS version 22. This study registered in the Iranian Registry of Clinical Trials (IRCT20231001059572N1).</p> Results <p>There was a significant difference between the intervention and control groups in terms of duration of mechanical ventilation (<i>p</i> &lt; 0.001), length of ICU stay (<i>p</i> &lt; 0.001), and successful weaning from the ventilator (<i>p</i> &lt; 0.001). In all three dimensions, the intervention group showed better outcomes. However, there was no significant difference between the two groups in terms of ICU mortality (<i>p</i> = 0.202) and self-extubation (<i>p</i> = 0.787). Being in the intervention group was the strongest predictive factor for length of ICU stay (β = −8.268, <i>p</i> &lt; 0.001) and duration of mechanical ventilation (β = −3.906, <i>p</i> = 0.003). No major harms or unintended adverse effects were reported related to the intervention.</p> Conclusion <p>Implementation of a PVA management protocol was associated with improved clinical outcomes, including reduced duration of mechanical ventilation, shorter ICU stays, and higher rates of successful weaning. Given its simplicity, cost-effectiveness, and the favorable results observed, broader adoption of this protocol in ICU settings is recommended. Further studies are warranted to confirm these findings and examine their generalizability across different clinical contexts.</p>