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Catastrophic spontaneous spinal epidural hematoma (SSEH) following thrombolysis poses a complex intersection of neurosurgical and cardiological challenges. This case report presents the institutional experience of a 66-year-old female who developed rapid-onset compressive myelopathy after thrombolysis for inferior wall myocardial infarction with injection streptokinase. SSEH, although rare, demands prompt recognition due to its potential for permanent neurologic injury and mortality. The discussion highlights the clinical significance, anatomical considerations, and multidisciplinary approach requisite for accurate diagnosis and effective management of SSEH. The conclusion underscores the necessity for clinicians, particularly cardiologists administering thrombolytic therapies, to consider SSEH in postthrombolysis patients presenting with neurological deficits.