BACKGROUND Nasopharyngeal carcinoma (NPC) is a commonly encountered type of tumor. Fluorouracil (FU) is an effective treatment providing satisfactory oncologic outcomes in nasopharyngeal carcinoma patients. We describe a unique case of colonic perforation in an NPC patient treated with FU. Thus far, only two cases of intestinal perforation associated with FU treatment have been reported. We hope that the analysis of the relationship between the adverse effects of FU and physiological factors will help to reduce the incidence of colonic perforation in patients with nasopharyngeal carcinoma treated with FU. CASE SUMMARY A 67-year-old female patient suffered from NPC stage pT3N2M0. She had a history of three surgical procedures: Partial enterectomy, partial sigmoidectomy, and sigmoidostomy. After the administration of 2.75 g FU, a bloody stool appeared and the patient developed abdominal pain. Subsequent examination indicated colitis and intestinal perforation. CONCLUSION FU is a commonly used drug in NPC chemotherapy. The most common adverse effect of FU is gastrointestinal reaction, and the colonic perforation found here is thought to be caused by gastrointestinal mucosal injury consequential to the FU treatment. When selecting chemotherapy drugs, their side effects and the physical condition of patients should be considered, particularly in patients with a history of gastrointestinal surgery.