Minoxidil is an antihypertensive medication used to control blood pressure that is resistant to three or more antihypertensive medications including diuretics. There have only been a few reported cases of minoxidil-induced pleuropericardial effusion with anasarca. Here, we discuss the case of a 70-year-old male with a history of uncontrolled hypertension who presented to the hospital with swelling of the extremities. He was on minoxidil 10 mg twice a day and complained of generalized body swelling and extremity pain with symptoms of dyspnea on exertion, paroxysmal nocturnal dyspnea, weight gain, abdominal distention, and intermittent, throbbing extremity pain (8/10). The patient denied a history of cardiac disease, pulmonary embolism, deep vein thrombosis, and malignancy. His vitals were stable with a blood pressure of 152/67 mmHg. The physical examination findings were significant for positive jugular vein pressure, bilateral crackles at the lung bases with abdominal distention, fluid thrill, and flank edema. The extremities showed pitting edema in the upper and lower extremities that were tender to palpation. Laboratory results were only significant for uremia and elevated brain natriuretic peptide. Electrocardiography, echocardiography, and CT of the chest and abdomen exhibited findings consistent with pericardial effusion, pleural effusion, abdominal ascites, and anasarca in the soft tissues of the axilla and chest wall. After discontinuation of minoxidil and starting intravenous diuretics, the patient showed clinical improvement. This case report reviews and explains that minoxidil-induced anasarca should be considered as a differential diagnosis in patients taking minoxidil as knowledge of this rare finding may lead to early diagnosis and management.