Apixaban has been associated with prolongation of the international normalized ratio (INR), but data surrounding the extent of elevation and its clinical significance are limited. Due to interaction between apixaban and the prothrombin assay, elevations in INR in patients receiving apixaban are common and not always grounds for concern. However, in high risk patients, elevations can represent a need for closer monitoring. This case summarizes an 82-year-old woman with a history of atrial fibrillation and left middle cerebral artery strokes with no residual deficits. She presented with right-sided hemiparesis and aphasia and underwent a mechanical thrombectomy with TICI 2b recanalization of a left M1 occlusion. Post-thrombectomy, she was found to have a left atrial thrombus and 10 days later was started on apixaban 5 mg twice daily. On the fourth day of apixaban therapy, she experienced an INR increase to 2.3, prompting initiation of a vitamin K challenge for nutritional deficiency. Despite initial improvement, her INR increased to 2.7 a week after apixaban was initiated, coinciding with a decline in mental status and an apixaban peak level of 435.6 ng/mL (reference range 91-321 ng/mL). A computed tomography (CT) scan of her head showed new intracranial hemorrhage in the area of her previous infarction, prompting apixaban reversal with andexanet alfa. Unfortunately, the patient expired. This case report highlights the importance and difficulty in performing therapeutic drug monitoring in patients receiving oral anti-factor Xa inhibitors, revealing a downside to administration of high-risk medications that do not have readily available monitoring.