Oxygen is used frequently to relieve dyspnea in patients with advanced illness. The objective of this study was to critically appraise the scientific basis for oxygen therapy as a therapeutic intervention to manage dyspnea at rest in patients with advanced disease. A systematic search of all relevant databases was done using MeSH terms and appropriate key words. Both investigators reviewed 294 citations and possible articles were retrieved. Using the inclusion and exclusion criteria of the research question, five articles were found to be relevant to the question. The articles were graded according to the study design and qualitatively compared. No systematic reviews of the intervention exist. Study designs were case series and case control studies. These primary studies had small samples and did not have matched or cohort controls, therefore providing only level 4 evidence. There was only a total of 83 patients and the majority of the patients were hypoxic and already on oxygen. This systematic review and critical appraisal found low-grade scientific evidence that oxygen and airflow improve dyspnea in some patients with advanced disease at rest. However, there is no evidence to identify which patients will benefit from airflow or supplemental oxygen or to determine when to use airflow versus supplemental oxygen. Further research is required to provide scientific evidence to evaluate oxygen and airflow effectiveness and determine the place of oxygen and airflow in the management of dyspnea at rest in patients with advanced disease.