Duodenal perforation consequent to prior surgery is a rare but severe complication carrying serious consequences if not promptly managed. This study aims to identify the best treatment pathway available to date. This is a systematic review registered to PROSPERO. The literature research was conducted on Ovid Medline, Embase, and Cochrane up to February 2022 to identify all papers reporting surgical-related duodenal perforations. Twelve articles were included. Most of these studies were case reports or case series. The most common cause of perforation was laparoscopic cholecystectomy (72.7%). The median time to symptom appearance was 2 days. Most of these perforations were severe injuries located in the first portion of the duodenum. Only one patient was treated with a non-interventional conservative management, which failed. Five patients were managed with interventional non-surgical treatments: 4 with endoscopy (50% failure) and one with a percutaneous occluder. Different surgical treatments were reported: direct suture (100% failure), direct suture and T-tube duodenostomy (75% failure), simple abdominal drainage, and suture with pyloric exclusion. Further extensive surgeries were also reported. The overall mortality rate was 13.6%, with a median hospital stay of 38.5 days. This review shows a wide spectrum of managements for patients with duodenal perforation related to prior surgery. The decision on which treatment to adopt must consider patient’s clinical setting and duodenal defect characteristics (size, site, and time to diagnosis). A tentative treatment flowchart is provided, although larger sample size studies are needed to obtain a treatment pathway based on evidence.