The opioid epidemic endangers not only public health but also social and economic welfare. Growing clinical evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke and negatively impact poststroke recovery. In addition, NLRP3 inflammasome activation has been related to several cerebrovascular diseases, including ischemic stroke. Interestingly, an increase in NLRP3 inflammasome activation has also been reported in chronic opioid exposure. 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. Our results demonstrate that chronic opioid exposure can compromise the integrity of the BBB and elevate the generation of reactive oxygen species (ROS), resulting in endothelial mitochondrial dysfunction and apoptosis activation. We also provide evidence that opioid exposure enhances inflammasome activation and inflammatory responses and increases the severity of an ischemic stroke. The antioxidant N-acetylcysteine ameliorated these opioid-induced alterations and accelerated the poststroke tissue restoration and functional recovery processes in opioid-exposed mice. Importantly, there was also a significant decrease in ischemic stroke damage in the NLRP3-deficient mice with chronic opioid exposure as compared with wild-type controls. These findings indicate that chronic exposure to prescription opioids impacts the outcome of ischemic stroke by damaging microvascular cerebral integrity through inflammasome activation and mitochondrial dysfunction.