Patients with COVID-19 may suffer from hemorrhagic complications. Our article highlights two cases of COVID-19-infected patients, who suffered severe epistaxis after initiation of intravenous recombinant tissue plasminogen activator (IV-rtPA) for acute ischemic stroke, followed by a sudden decline in their clinical status and ultimately leading to death within days. Given the global impact and mortality of COVID-19, it is essential to be aware of its unusual presentation and improve therapeutic strategies. We present two cases of individuals who suffered from a large vessel occlusion of and were candidates for both IV-rtPA and mechanical thrombectomy. They received IV-rtPA but had epistaxis so severe that they were not able to receive MT and died within the next few days. There are many potential mechanisms by which epistaxis can happen in an individual with COVID-19 who received IV-rtPA including invasion of the nasal mucosa and endothelium through angiotensin-converting enzyme 2 receptors by the virus. We also hypothesize that the coagulation abnormality seen in COVID-19 patients can be potentiated by the use of treatments such as IV-rtPA. We review these issues with a diagram illustrating the possible mechanisms.