Intravenous tissue plasminogen activator (tPA) increases survival rates without sequelae in acute ischemic stroke. Complications and management of this treatment have become more important with the increasing use of tPA. An 80-year-old male patient was admitted with a sudden-onset speech disorder and loss of strength in his right arm, which started 3 hours ago. Magnetic resonance imaging revealed acute ischemia localized in the left insular cortex. Lip and tongue swelling, difficulty in speaking, and deepening in voice were observed in the 30th minute of infusion. There was mild respiratory distress. Orolingual angioedema was diagnosed. He completely recovered after treatment. Angioedema is a rare but potentially life-threatening complication of tPA. When this clinical symptom occurs, it should be recognized and treated quickly. This report aims to reveal the relationship of this rare complication with the localization of the ischemia.