Background: Mechanical ventilation is an essential component of critical care but is associated with complications such as ventilator-induced diaphragm dysfunction, prolonged weaning, and increased mortality. Identifying effective strategies to optimize liberation from mechanical ventilation remains a priority to improve patient outcomes. Objectives: This systematic review aimed to evaluate evidence on weaning and extubation strategies, predictive parameters, and pathophysiological mechanisms influencing extubation outcomes in critically ill patients. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Scopus, and Web of Science was conducted up to 2024. Eligible studies included randomized controlled trials, observational studies, crossover trials, and narrative reviews assessing ventilation strategies, extubation outcomes, or predictors of successful weaning. Two independent reviewers performed screening, data extraction, and risk of bias assessment. Results: Nine studies met inclusion criteria, comprising seven randomized controlled trials, one crossover trial, and one narrative review. Sample sizes ranged from 23 preterm infants to 604 critically ill adults. Structured weaning protocols, such as spontaneous awakening and breathing trials, were associated with increased ventilator free days, reduced ICU stay, and lower mortality. Lactate-guided therapy facilitated earlier liberation and reduced hospital mortality. Post-extubation noninvasive ventilation (NIV) reduced reintubation in high-risk and obese patients, while high-flow nasal cannula (HFNC) was non-inferior in broader populations and better tolerated. In neonates, cardiorespiratory variability measures predicted extubation success with moderate accuracy. The narrative review underscored unique challenges in obese patients, advocating individualized ventilatory strategies. Conclusion: Evidence supports the use of structured weaning protocols, risk-stratified use of NIV or HFNC, and physiologic predictors to optimize extubation outcomes. Preventive strategies against respiratory muscle dysfunction and tailored approaches for high-risk groups, including obese and neonatal patients, are essential. Future research should refine predictive models and evaluate interventions targeting ventilator-induced diaphragm dysfunction.