Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed throughout the world. Their adverse effects on the upper gastrointestinal (GI) tract are well documented and well known among clinicians and often mitigated against by coprescribing proton pump inhibitors. This case exemplifies the lesser-known lower GI adverse effects of NSAIDS. A 55-year-old patient took a large mixed overdose including more than 11 g of diclofenac. He went onto require subtotal colectomy following widespread perforations of an ulcerated large bowel as a direct result of exposure to a high-dose of NSAIDs. However, the upper GI tract remained relatively unaffected in comparison. This case highlights important lessons from recent literature identifying an increasing incidence of lower GI complications of NSAIDS, the limited protective effect of PPIs on the lower GI tract and the need for clinicians to now consider the integrity of the whole GI tract when prescribing NSAIDS.