Stroke is an acute neurologic injury caused by ischemia or hemorrhage that stems from a wide range of pathologies, with high rates of morbidity, mortality, and disability. Thrombolysis and endovascular thrombectomy are the only FDA approved methods for the treatment of acute ischemic stroke (AIS), but the clinical benefits of reperfusion therapy are significantly limited by hemorrhagic transformations (HT), resistance to thrombolytic drugs, and reperfusion no-reflow. Although the factors leading to these problems are complex, neutrophils play the most critical role in them. Based on the latest research progress in recent years, this review focuses on the role of neutrophils in mediating the pathophysiological events of AIS, the specific mechanisms by which neutrophils cause HT, thrombolytic drug resistance, and no-reflow after reperfusion therapy, as well as strategies targeting neutrophils to prevent or alleviate these complications following reperfusion therapy, offering new insights for the clinical therapy and drug development of ischemic stroke.