The etiology of post-operative ileus is usually multifactorial, but increased catecholamines have been implicated as an important cause. We present a case of catecholamine-induced prolonged post-operative ileus treated successfully with Pyridostigmine. A 70-year-old male underwent a low-anterior resection and diverting loop ileostomy for rectal cancer. Immediately post-operatively he developed refractory hypertensive urgency and a small bowel ileus. Biochemical testing revealed markedly elevated 24-hour urinary metanephrines and normetanephrines. However, radiologic studies failed to identify a pheochromocytoma. The ileus persisted despite employing a multimodal regimen consisting of avoidance of narcotic pain medications, gastric decompression via a nasogastric tube, maintenance of normal levels of electrolytes, parenteral nutritional support, and early mobilization. Two weeks after the surgery the patient was treated with oral Pyridostigmine with appropriate return of bowel function. Excessive circulating catecholamines play an important role in the etiology of refractory post-operative ileus, and cholinesterase inhibitors such as Pyridostigmine could be used as an effective treatment in such cases.