Ischemic stroke is one of the leading causes of death and disability. Occlusion and reperfusion of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS) that contribute to brain cell death and dysfunction of the blood-brain barrier (BBB) via oxidative stress. BBB disruption influences the pathogenesis of ischemic stroke by contributing to cerebral edema, hemorrhagic transformation, and extravasation of circulating neurotoxic proteins. An improved understanding of mechanisms for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead to improved treatment paradigms for ischemic stroke. Unfortunately, progress in developing ROS targeted therapeutics that are effective for stroke treatment has been slow. Here, we review how ROS are produced in response to I/R injury, their effects on BBB integrity (i.e., tight junction protein complexes, transporters), and the utilization of antioxidant treatments in ischemic stroke clinical trials. Overall, knowledge in this area provides a strong translational framework for discovery of novel drugs for stroke and/or improved strategies to mitigate I/R injury in stroke patients.