Mechanical ventilation (MV) is designed to support work of breathing and maintain adequate gas exchange. However, long-term use of MV leads to diaphragm atrophy, overall weakening of respiratory muscles and hence ventilator dependence. The 14-day weaning rate was only 38.5% in our intensive care unit. A specific project was set up aiming at raising the MV weaning rates. The potential causes of low weaning rates were assessed and categorized as follows: (1) patient factor: weakness of respiratory muscles, delirium, pain and discomfort; (2) medical staff factor: task missing during work shift on holidays, premature extubation demanding quick reintubation, and inadequate familiarity with related care and weaning protocol; (3) policy factor: lack of relevant education. To solve the above problems, ABCDEF bundle was adopted as the framework with interdisciplinary cooperation, including: (1) lung rehabilitation exercises, (2) sleep promotion programs, (3) alternative pain management, (4) standard operating procedures for work shift on holidays concerning extubation, (5) case conferences on patients with ventilators, and (6) educational programs for medical staffs. After implementing the strategy, the 14-day weaning rates raised 77.8%, while the delayed extubation rate was reduced from 13.6% to 0%, and the reintubation rate was reduced from 8.5% to 0%. This strategy with interdisciplinary collaboration effectively increased the weaning rate of MV and improved the quality of medical care.