The recent coronavirus disease 2019 (COVID-19) pandemic produced high and excessive demands for hospitalizations and equipment with depletion of critical care resources. The results of these extreme therapeutic efforts have been sobering. Further, we are months away from a robust vaccination effort, and current therapies provide limited clinical relief. Therefore, several empirical oxygenation support initiatives have been initiated with intermittent hyperbaric oxygen (HBO) therapy to overcome the unrelenting and progressive hypoxemia during maximum ventilator support in intubated patients, despite high FiO2. Overall, few patients have been successfully treated in different locations across the globe. More recently, less severe patients at the edge of impending hypoxemia were exposed to HBO preventing intubation and obtaining the rapid resolution of symptoms. The few case descriptions indicate large variability in protocols and exposure frequency. This summary illustrates the biological mechanisms of action of increased O2 pressure, hoping to clarify more appropriate protocols and more useful application of HBO in COVID-19 treatment.