Hypoxemia, caused by disrupted vasculature, is a key factor that limits wound healing. Correcting hypoxemia through the administration of supplemental oxygen (O₂) can have significant beneficial impact on wound healing in the perioperative and outpatient settings. Beyond its role as a nutrient and antibiotic, O₂ may support vital processes such as angiogenesis, cell motility, and extracellular matrix formation. Recent discoveries highlight a novel aspect, addressing the role of O₂ in wound healing via the production of reactive oxygen species (ROS). Almost all wound-related cells possess specialized enzymes that generate ROS (including free radicals and H₂O₂) from O₂. Defect in these enzymes is associated with impaired healing. Low wound pO₂ is expected to compromise the function of these enzymes. At low concentrations, ROS serve as cellular messengers to support wound healing. The use of systemic hyperbaric O₂ therapy presents potential advantages, as well as risks. There is evidence to suspect that the use of pressure and systemic pure O₂ may not be essential in wound care. Elimination of these factors by using sub-pure systemic O₂ under normobaric conditions may significantly minimize the risk of O₂ toxicity. Furthermore, opportunities to treat dermal wounds using topical O₂ therapy warrant further investigation. Given that many growth factors require ROS for their function, it is reasonable to assume that approaches to correct wound pO₂ will serve as an effective adjunct in treating chronic wounds.