In patients with critically ill COVID-19 pneumonia, lower airways are filled with plenty of highly viscous exudates or mucus, leading to airway occlusion. The estimation of airway opening pressures and effective mucus clearance are therefore two issues that clinicians are most concerned about during mechanical ventilation. In this study we retrospectively analyzed respiratory data from 24 critically ill patients with COVID-19 who received invasive mechanical ventilation and recruitment maneuver at Jinyintan Hospital in Wuhan, China. Among 24 patients, the mean inspiratory plateau pressure was 52.4 ± 4.4 cmH₂O (mean ± [SD]). Particularly, the capnograms presented an upward slope during the expiratory plateau, indicting the existence of airway obstruction. A computational model of airway opening was subsequently introduced to investigate possible fluid dynamic mechanisms for the extraordinarily high inspiratory plateau pressures among these patients. Our simulation results showed that the predicted airway opening pressures could be as high as 40–50 cmH₂O and the suction pressure could exceed 20 kPa as the surface tension and viscosity of secretion simulants markedly increased, likely causing the closures of the distal airways. We concluded that, in some critically ill patients with COVID-19, limiting plateau pressure to 30 cmH₂O may not guarantee the opening of airways due to the presence of highly viscous lower airway secretions, not to mention spontaneous inspiratory efforts. Active airway humidification and effective expectorant drugs are therefore strongly recommended during airway management.