Pulmonary embolism (PE) is a known risk of lumbar spinal fusion surgery that can lead to sudden and unexpected death. Treatment often involves systemic anticoagulation when the risk of potentially fatal hemodynamic deterioration is judged to outweigh the risk of epidural hematoma and paralysis. Acute massive pulmonary embolism with obstruction of more than 50% of the pulmonary arterial tree causes right heart failure, hypotension, and often rapid death, and may require aggressive medical intervention with thrombolytic agents like alteplase, though in the postoperative period this entails an extremely high risk of bleeding and the associated potential neurologic morbidity. We report the first case of intraoperative thrombolytic therapy during spine surgery in a 68-year-old female who developed a massive PE with cardiac arrest while undergoing lumbar instrumented fusion surgery in the prone position and detail the postoperative course that was complicated by severe bleeding.