Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare potentially fatal disease. We present a case of cocaine-related SISMAD in a patient with abdominal pain. A 38-year-old African American male with hypertension and alcohol, cocaine, and tobacco abuse presented with abdominal pain and recent cocaine use. A CT angiogram revealed SISMAD; he was treated with conservative management. Cocaine and SISMAD share similar pathophysiologic mechanisms pertaining to vascular smooth muscle cell apoptosis and increased shear stress at fixed vascular positions. Our report emphasizes the need to consider cocaine abuse in SISMAD pathophysiology, risk stratification, and treatment algorithms in future studies.