Background Prolonged duration of mechanical ventilation is associated with higher mortality and increased patient complications; conventional physician-directed weaning methods are highly variable and permit significant time that weaning is inefficient and ineffective. Objectives The primary objective of this quality improvement project was to implement a registered nurse (RN)– and respiratory therapist (RT)-driven mechanical ventilation weaning protocol in a medical intensive care unit (ICU) at a tertiary care academic medical center. Methods This quality improvement project used a quasi-experimental design with a retrospective usual care group who underwent physician-directed (conventional) weaning (n = 51) and a prospective intervention group who underwent protocol-directed weaning (n = 54). Outcomes included duration of mechanical ventilation, ICU length of stay, reintubation rates, and RN and RT satisfaction with the weaning protocol. Results Patients in the RN- and RT-driven mechanical ventilation weaning protocol group had significantly lower duration of mechanical ventilation (74 vs 152 hours; P = .002) and ICU length of stay (6.7 vs 10.2 days; P = .031). There was no significant difference in reintubation rates between groups. Staff surveys indicate that both RN and RTs were satisfied with the process change. Discussion Implementation of a multidisciplinary mechanical ventilation weaning protocol is a safe and effective way to improve patient outcomes and empower ICU staff.