A duodenal perforation is a serious complication that can occur during endoscopic retrograde cholangiopancreatography (ERCP), particularly if it is associated with therapeutic endoscopic sphincterotomy. Therefore, it is crucial to identify and manage it early to achieve the best possible outcome. Conservative management may be attempted; however, surgical intervention is required if signs of sepsis or peritonitis are present. In this case report, we present the case of post-ERCP duodenal perforation in a 33-year-old female with sickle cell disease who presented on account of abdominal pain. The patient was diagnosed with post-ERCP duodenal perforation, type 4 according to the Stapfer classification. She was subsequently treated conservatively with intravenous antibiotics, bowel rest, and serial abdominal exams. The patient noted significant interval improvement in symptoms and was subsequently discharged home. The early detection and management of suspected complications of ERCP provide a critical prognostic value.