Stroke, one of the most debilitating cerebrovascular and nuerological diseases, is a serious life-threatening condition and a leading cause of long-term adult disability and brain damage, either directly or by secondary complications. Most effective treatments for stroke are time dependent such as the only FDA-approved therapy, reperfusion with tissue-type plasminogen activator; thus, improving tissue oxygenation with normobaric hyperoxia (NBO) has been considered a logical and potential important therapy. NBO is considered a good approach because of its potential clinical advantages, and many studies suggest that NBO is neuroprotective, reducing ischemic brain injury and infarct volume in addition to improving pathologic and neurobehavorial outcomes. However, increased reactive oxygen species (ROS) generation may occur when tissue oxygen level is too high or too low. Therefore, a major concern with NBO therapy in acute ischemic stroke is the potential increase of ROS, which could exacerbate brain injury. The purpose of this review is to critically review the current literature reports on the effect of NBO treatment on ROS and oxidative stress with respect to acute ischemic stroke. Considering the available data from relevant animal models, NBO does not increase ROS or oxidative stress if applied for a short duration; therefore, the potential that NBO is a viable neuroprotective strategy for acute ischemic stroke is compelling. The benefits of NBO may significantly outweigh the risks of potential increase in ROS generation for the treatment of acute ischemic stroke.