Multiple medications have been related to triggering headache attacks or worsening headache frequency or severity in patients with migraine disease. However, the impact of direct oral anticoagulants on headache frequency and severity in patients with migraine disease is unclear. Current literature is scarce and controversial. A 45-year-old male with a history of migraine with aura for the last 20 years underwent percutaneous transcatheter closure of an atrial septal defect due to right ventricular enlargement and systolic dysfunction. The intervention was complicated by postprocedural atrial fibrillation, for which he was started on apixaban. Shortly after starting the apixaban, the patient experienced an increase in the frequency and severity of his migraine with aura episodes that were persistent until he discontinued this medication 7 months later. Following the discontinuation of apixaban, the patient's frequency and severity of migraine episodes returned to baseline almost immediately. Novel oral anticoagulants, including apixaban, may be associated with an increase in the frequency and severity of migraine attacks in patients with migraine disease. Larger observational studies are required to investigate further the impact of direct oral anticoagulants on migraine disease.