BACKGROUND The pathophysiological characteristics of severe pneumonia complicated by respiratory failure comprise pulmonary parenchymal changes leading to ventilation imbalance, alveolar capillary injury, pulmonary edema, refractory hypoxemia, and reduced lung compliance. Prolonged hypoxia can cause acid-base balance disorder, peripheral circulatory failure, blood-pressure reduction, arrhythmia, and other adverse consequences. AIM To investigate sequential mechanical ventilation’s effect on severe pneumonia complicated by respiratory failure. METHODS We selected 108 patients with severe pneumonia complicated by respiratory failure who underwent mechanical ventilation between January 2018 and September 2020 at the Luhe Hospital’s Intensive Care Unit and divided them into sequential and regular groups according to a randomized trial, with each group comprising 54 patients. The sequential group received invasive and non-invasive sequential mechanical ventilation, whereas the regular group received invasive mechanical ventilation. Blood-gas parameters, hemodynamic parameters, respiratory mechanical parameters, inflammatory factors, and treatment outcomes were compared between the two groups before and after mechanical-ventilation treatment. RESULTS The arterial oxygen partial pressure and stroke volume variation values of the sequential group at 24, 48, and 72 h of treatment were higher than those of the conventional group ( P < 0.05). The carbon dioxide partial pressure value of the sequential group at 72 h of treatment and the Raw value of the treatment group at 24 and 48 h were lower than those of the conventional group ( P < 0.05). The pH value of the sequential group at 24 and 72 h of treatment, the central venous pressure value of the treatment at 24 h, and the Cst value of the treatment at 24 and 48 h were higher than those of the conventional group ( P < 0.05). The tidal volume in the sequential group at 24 h of treatment was higher than that in the conventional group ( P < 0.05), the measured values of interleukin-6 and tumor necrosis factor-α in the sequential group at 72 h of treatment were lower than those in the conventional group ( P < 0.05), and the total time of mechanical ventilation in the sequential group was shorter than that in the conventional group, with a statistically significant difference ( P < 0.05). CONCLUSION Treating severe pneumonia complicated by respiratory failure with sequential mechanical ventilation is more effective in improving respiratory system compliance, reducing inflammatory response, maintaining hemodynamic stability, and improving patient blood-gas levels; however, from this study’s perspective, it cannot reduce patient mortality.