Oxygen is the most commonly used therapy in hospitalized patients with COVID-19. In those patients who develop worsening pneumonia and acute respiratory distress syndrome (ARDS), high concentrations of oxygen may need to be administered for prolonged time periods, often together with mechanical ventilation. Hyperoxia, although lifesaving and essential for maintaining adequate oxygenation in the short-term, may have adverse long-term consequences upon lung parenchymal structure and function. How hyperoxia per se impacts lung disease in COVID-19 has remained largely unexplored. Numbers of experimental studies have previously established that hyperoxia is associated with deleterious outcomes inclusive of: perturbations in immunologic responses; abnormal metabolic function and alterations in hemodynamics and alveolar barrier function. Such changes may ultimately progress into clinically evident lung injury, adverse remodeling and result in parenchymal fibrosis when exposure is prolonged. Given that significant exposure to hyperoxia in patients with severe COVID-19 may be unavoidable to preserve life, these sequelae of hyperoxia, superimposed on the cytopathic effects of SARS-CoV-2 virus may well impact pathogenesis of COVID-19-induced ARDS.