Mechanical ventilation is life-saving but prolonged support increases the risk of ventilator-associated complications, muscle weakness, and death. Evidence-based weaning protocols have been developed to standardize liberation from the ventilator, yet practice remains highly variable. This systematic review summarizes randomized and prospective studies evaluating protocolized and technology-assisted weaning strategies in adult intensive care units. Electronic databases (MEDLINE, Embase, Cochrane Library, and Web of Science) were searched for clinical trials and prospective cohorts that compared protocol-based weaning with usual care or alternative strategies. Six unique studies were included: daily screening with spontaneous breathing trials, nurse-directed protocols, different spontaneous breathing trial durations, computer-driven closed-loop systems, and protocols incorporating rapid shallow breathing index and diaphragmatic rapid shallow breathing index. Across trials, protocolized strategies consistently shortened the duration of mechanical ventilation or weaning without increasing reintubation, although the magnitude of benefit varied by intervention and population. Closed-loop systems and diaphragm-based indices showed promise but were tested in relatively small or single-center cohorts. Despite decades of research, weaning remains a complex, multifactorial process. Available evidence supports the use of structured protocols and systematic daily screening, while newer automated and physiologic approaches require further validation in broader intensive care populations.