We present the case of a 36-year-old man with a history of type 2 diabetes mellitus (T2DM) and prior plantar necrotizing fasciitis, who initially improved on semaglutide but later experienced weight gain and elevated hemoglobin A1C (HbA1c) levels. After switching to tirzepatide, he developed nausea, epigastric pain, and vomiting. Shortly after increasing the tirzepatide dosage, he presented to the emergency room with severe abdominal pain. Diagnostic imaging revealed an ulcer in the duodenal bulb with free air, indicating acute duodenal ulcer perforation. The patient underwent emergency surgery, and postoperative tests confirmed a