Our objective is to present a case of fatal multiple systemic emboli after intravenous thrombolysis for cardioembolic stroke. A 64-year-old woman with atrial fibrillation was admitted for evaluation of sudden consciousness disturbance, right hemiplegia, and aphasia. Diffusion-weighted imaging showed no early ischemic changes of the brain, and magnetic resonance angiography (MRA) showed occlusion of the left middle cerebral artery (MCA). One hour after initiation of 0.6 mg/kg of intravenous alteplase, the MCA was partially recanalized. Her symptoms disappeared the following day. We began intravenous heparin for secondary prevention of cardioembolic stroke. However, on the third day (52 hours after thrombolysis), she suddenly developed a coma and left hemiplegia. MRA showed acute occlusion of the right internal carotid artery (ICA). She developed acute kidney injury and sudden shock and then died of fatal cardiorespiratory arrest on the fourth day. Autopsy revealed occlusion of the mitral valve orifice by a spherical fresh red thrombus that led from the left atrial appendage. Acute embolic infarcts were identified in the spleen and right kidney, the latter secondary to occlusion of the right renal artery with fresh red thrombus. Intravenous thrombolysis and subsequent anticoagulation therapy may destabilize pre-existing intracardiac thrombus, potentially leading to recurrent stroke, multiple systemic embolisms, and the fatal “hole-in-one” effect.