—A hypothesis about the mechanism of radiosensitizing effect of hyperoxia during irradiation on the course and outcome of gastrointestinal radiation syndrome in the absence of significant modification of the course of hematopoietic radiation syndrome is presented. The important role of an increased production of reactive oxygen species (ROS) in hyperoxia in promoting gastrointestinal radiation injury in the absence of a significant contribution of the “oxygen effect” to this process is considered. The role of the accumulation of the toxic effects of ROS under repeated hyperoxia with exposure to fractionated irradiation in exacerbating acute radiation syndrome is emphasized. Attention is paid to the role of the preliminary daily stress effect of vibration on the potentiation of the radiosensitizing effect of hyperoxia on the course of gastrointestinal radiation syndrome. The metabolic changes in the regulation of the energy supply of the body under combined exposure to ionizing radiation and hyperoxia are analyzed. Possible mechanisms of radiomitigating effect of hyperoxia on the hematopoietic tissue, manifested during short-term 100% oxygen breathing before or immediately after irradiation of animals are considered. The signaling role of ROS and the cytostatic effect caused by hyperoxia in enhancing the postradiation recovery of hemopoietic tissue is emphasized.