Oxygen is an undisputed key factor in wound healing. Adequate oxygen pressure in tissues allows for cell growth and proliferation, necessary for wound healing. In the case of peripheral arterial disease leading to hypoxemia, oxygen supplementation is beneficial. The roles and validity of topical and systemic oxygen therapy in wound healing is debated. Topical oxygen therapy (TOT) is delivered at 100% oxygen saturation and has been demonstrated to increase the pO2 levels within the wound base center, decrease the size of the wound, and decrease the time to wound healing compared to patients that did not undergo topical oxygen therapy. Alternatives to topical oxygen therapy are systemic oxygen therapy including hyperbaric oxygen therapy and inspired oxygen therapy. Systemic oxygen therapy carries the risk of oxygen organ toxicity as the result of an oxidative stress and genotoxicity state. Topical O2 therapy is a viable option for chronic wounds, with its demonstrated effects on decrease in wound size and time to healing. Adjunctive clinical wound debridement’s decrease the necrotic debris and therefore the topical oxygen diffusion distance optimizing the therapy effect.