Background: Mechanical ventilation is the main supportive treatment of severe cases of COVID-19-associated ARDS (C-ARDS). Weaning failure is common and associated with worse outcomes. We investigated the role of respiratory drive, assessed by monitoring the electrical activity of the diaphragm (EAdi), as a predictor of weaning failure. Methods: Consecutive, mechanically ventilated patients admitted to the ICU for C-ARDS with difficult weaning were enrolled. Blood gas, ventilator, and respiratory mechanic parameters, as well as EAdi, were recorded at the time of placement of EAdi catheter, and then after 1, 2, 3, 7, and 10 days, and compared between patients with weaning success and weaning failure. Results: Twenty patients were enrolled: age 66 (60–69); 85% males; PaO2/FiO2 at admission 148 (126–177) mmHg. Thirteen subjects (65%) were classified as having a successful weaning. A younger age (OR(95%CI): 0.02 (0.01–0.11) per year), a higher PaO2/FiO2 ratio (OR(95%CI): 1.10 (1.01–1.21) per mmHg), and a lower EAdi (OR(95%CI): 0.16 (0.08–0.34) per μV) were associated with weaning success. Conclusion: In critically ill patients with moderate–severe C-ARDS and difficult weaning from mechanical ventilation, a successful weaning was associated with a lower age, a higher oxygenation, and a lower respiratory drive, as assessed at the bedside via EAdi monitoring.