Supplemental oxygen is a standard therapeutic intervention for critically ill patients such as patients suffering from cardiac arrest, myocardial ischemia, traumatic brain injury, and stroke. However, the optimal oxygenation targets remain elusive owing to the paucity and inconsistencies in the relevant literature. A comprehensive analysis of the available scientific evidence was performed to establish the relative efficacy of the lower and higher oxygenation targets. A systematic literature search was conducted in PubMed, MEDLINE, and Scopus databases from 2010 to 2023. Further, Google Scholar was also searched. Studies evaluating the efficacy of oxygenation targets and the associated clinical outcomes were included. Studies that included participants with hyperbaric oxygen therapy, chronic respiratory diseases, or extracorporeal life support were excluded. The literature search was performed by two blinded reviewers. A total of 19 studies were included in this systemic review, including 72,176 participants. A total of 14 randomized control trials were included. A total of 12 studies investigated the efficacy of lower and higher oxygenation targets in ICU-admitted patients, and seven were assessed in patients with acute myocardial infarction and stroke. For ICU patients, the evidence was conflicting, with some studies showing the efficacy of conservative oxygen therapy while others reported no difference. Overall, nine studies concluded that lower oxygen targets are favorable. However, most studies (n=4) in stroke and myocardial infarction patients showed no difference in lower or higher oxygenation targets whereas only two supported lower oxygenation targets. Available evidence suggests that lower oxygenation targets result in either improved or equivalent clinical outcomes compared with higher oxygenation targets.