Given the pivotal roles of the blood–brain barrier (BBB) and oxidative stress in ischemic stroke pathophysiology, this study focuses on the impact of chronic exposure to prescription opioids on the integrity of cerebrovascular microvasculature, endothelial mitochondrial homeostasis, and the outcomes of ischemic stroke in male wild-type and NLRP3-deficient mice. This evidence concerns the gene NLRP3 and ischemic stroke.