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 ainfection. He received eradication therapy and was discharged about two months later. This case highlights the potential risk of duodenal perforation associated with tirzepatide, particularly in patients with untreatedinfection. The patient's worsening gastrointestinal symptoms and perforation after initiating tirzepatide suggest a potential drug-related effect, emphasizing the need for careful monitoring and further research into the mechanisms underlying gastrointestinal complications associated with tirzepatide.