A study investigated the use of an over-the-scope clip (OTSC) to close duodenal perforations during endoscopic ultrasound (EUS). Of 5,174 linear EUS procedures at Beijing Friendship Hospital from January 2017 to December 2024, four perforations (0.077%) occurred. All patients were female with a mean age of 76 years (range 71–81 years). Perforations were caused by a curved probe: three during diagnostic EUS and one after EUS-guided fine needle aspiration biopsy, with defect sizes from 3 mm to 15 mm. All perforations were successfully closed endoscopically by OTSC without surgery. The length of hospitalization was 32 to 92 days, depending on the clinical condition of the patients. Endoscopic closure of iatrogenic duodenal perforations up to 15 mm OTSC is safe and effective by experienced endoscopists. Early identification of perforation according to clinical symptoms and risk factors allows rapid endoscopic intervention to reduce complications.