A prothrombotic coagulopathy is commonly found in critically ill COVID‐19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID‐19 respiratory failure is a relatively preserved lung compliance and high Alveolar‐arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low‐compliance in ARDS. The COVID‐19 pandemic is overwhelming the world’s medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID‐19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.