Intravenous tissue plasminogen activator (tPA) remains the standard of treatment for patients presenting with acute ischemic stroke within the treatment window. In most patients, this often leads to an effective and life-prolonging intervention in the acute setting. This is, however, not without complications, which sometimes could be potentially fatal. Hemorrhagic complications, such as hemorrhagic conversion and bleeding, are the most discussed; however, facial angioedema has also been reported. We present a case of a 72-year-old African American male who developed right-sided ipsilateral orolingual angioedema 20 minutes after starting a tPA infusion. He was subsequently managed with antihistamine medications and steroids with interval resolution of symptoms. This case highlights the need for close monitoring while on tPA infusion, early detection, and management of potential facial angioedema complications. It also serves as a template for further studies focusing on preventative strategies for tPA-induced angioedema.