INTRODUCTION AND IMPORTANCE: Mesenteric laceration after screening colonoscopy is a rare and fatal complication. This case reported a giant hematoma due to a small intestinal mesenteric laceration after a screening colonoscopy. CASE DESCRIPTION: A 56-year-old woman complained of persistent dramatic abdominal pain after the screening colonoscopy. This patient has appendectomy, rheumatic heart disease, IgG4-related disease, type 2 diabetes mellitus, and coronary atherosclerotic heart disease. Blood tests showed hemoglobin concentration sharply fell to 87 g/L and computed tomography scans confirmed a 16.4 cm × 6.1 cm × 9.5 cm hematoma abdominal hematoma near the small intestine. Digital subtraction angiography consistently showed rough and disordered the fourth group of the superior mesenteric artery. The main diagnosis was mesenteric laceration of the small intestine following colonoscopy. The patient was treated with fasting, gastrointestinal decompression, rehydration, inhibition of gastric acid, and meropenem to fight infection, 4 U suspended red blood cells and 400 mL fresh frozen plasma. Finally, this patient was discharged after conservative treatment, and the abdominal hematoma was significantly shrunk after 3 months. CLINICAL DISCUSSION: Anticoagulants, a history of previous abdominal surgery, and IgG-RD leading to abdominal fibrosis were possible risk factors for mesenteric laceration. When the patient's condition is complex and has no absolute indication for surgery, conservative management could be appropriately considered. CONCLUSIONS: We reported a case of abdominal hematoma due to colonoscopy. The successful conservative therapy may provide a novel experience for intra-abdominal hematoma treatment.