Individuals with diabetes mellitus deal with chronic wounds that are associated with poor health outcomes and frequently result in immobility, infections, and amputations. For these patients, there is a significant amount of literature on the use of oxygen therapy and synthetic skin substitute therapy in promoting chronic wound healing. However, there is limited published evidence comparing the effectiveness of the two therapies. Our goal is to summarize existing evidence of how hyperbaric oxygen therapy and substitute skin therapy affect wound healing in 9 months. We use the PRISMA model to guide our review of literature found in the Nursing & Allied Health Database using hyperbaric oxygen therapy, skin substitute therapy, chronic wounds, and clinical studies to retrieve relevant studies. We narrowed our review of literature to 22 studies based on criteria that required no affiliations between therapies, manufacturers, or brands. We also reduced inclusion of literature that rated high with selection, performance, and reporting bias. With scholarship from different countries around the world dealing with patient populations with chronic wounds, our review yielded mixed results. Few studies reported hyperbaric oxygen therapy as a primary therapy for treating chronic wounds while others indicated no significant differences between the two. We recommend that more research and development on hyperbaric oxygen therapy and skin substitute therapy is necessary to determine the best options and clinical outcomes for a growing population of patients needing our best in medicine and treatment