Background: Caring for patients requiring mechanical ventilation is complex, and residents may lack adequate skill for managing these patients. Simulation-based mastery learning (SBML) is an educational model that trains clinicians to a high standard and can reduce complications. The mastery learning model has not been applied to ventilator management. Objective: The purpose of this study was to determine whether SBML, as compared with traditional training, is an effective strategy for teaching residents the skills necessary to manage patients requiring mechanical ventilation. Methods: We developed an SBML curriculum and a 47-item skills checklist to test ventilator management for patients with normal, restricted, and obstructed lung physiology. A minimum passing standard (MPS) on the checklist was set using the Mastery Angoff method. Residents rotating through the medical intensive care unit in Academic Year 2017-2018 were assigned to SBML or traditional training based on their medical intensive care unit team. The SBML group was pretested on a ventilator simulator using the skills checklist. They then received a 1.5-hour session (45 min didactic and 45 min deliberate practice on the simulator with feedback). At rotation completion, they were posttested on the simulator using the checklist until the MPS was met. Both SBML-trained and traditionally trained groups received teaching during daily bedside rounds and twice weekly didactic lectures. At rotation completion, traditionally trained residents were tested using the same skills checklist on the simulator. We compared pretest and posttest performance among SBML-trained residents and end of the rotation test performances between the SBML-trained and traditionally trained residents. Results: The MPS was set at 87% on the checklist. Fifty-seven residents were assigned to the SBML-trained group and 49 were assigned to the traditionally trained group. Mean checklist scores for SBML-trained residents improved from 51.4% (standard deviation [SD] = 17.5%) at pretest to 86.1% (SD = 7.6%) at initial posttest and 92.5% (SD = 3.7%) at final (mastery) posttest (both P < 0.001). Forty-two percent of residents required more than one attempt at the posttest to meet or exceed the MPS. At rotation completion, the traditionally trained residents had a mean test score of 60.9% (SD = 13.3%). Conclusion: SBML is an effective strategy to train residents on mechanical ventilator management. An SBML curriculum may augment traditional training methods to further equip residents to safely manage ventilated patients.