Background: Weaning from mechanical ventilation is important step in the recovery of critically ill patients. Nurses play a central role in this process due to their continuous patient monitoring and involvement in breathing trials. Variability in training, protocol access, and institutional support affect the effectiveness of nurse-led weaning practices. Objective: This systematic review aimed to evaluate the role of nurses in the weaning process from mechanical ventilation in intensive care settings, focusing on knowledge levels, clinical practices, protocol implementation, and associated patient outcomes. Methods: A systematic search was conducted in PubMed, Scopus, CINAHL, and Web of Science databases from 2005 to 2025 according to PRISMA 2020 guidelines. We include studies involved adult ICU patients, focused on nurse roles in ventilator weaning, and reported original data. Eleven studies met the inclusion criteria. Data were extracted and synthesized qualitatively. Risk of bias was assessed using appropriate tools for each study design. Results: The included studies used qualitative (n = 3), observational or cohort (n = 4), randomized controlled trial (n = 2), mixed-methods (n = 1), and retrospective chart review (n = 1) designs. Findings indicate the effectiveness of nurse-led or protocolized weaning strategies to reduce mechanical ventilation duration and ICU length of stay. Nurses’ clinical experience, training, and the availability of standardized protocols affected outcomes. Variability in documentation, autonomy, and decision-making roles persisted across settings. Conclusion: Nurses are integral to the ventilator weaning process, mainly when supported by structured protocols and training. Which enhance nurse autonomy, standardizing weaning practices, and fostering interdisciplinary collaboration can improve weaning outcomes and ICU efficiency.