Postoperative pancreatic fistula (POPF) is associated with a mortality of up to 25% apart from significant morbid sequelae related to abdominal sepsis and post pancreatectomy hemorrhage. Numerous strategies to curtail the risk of POPF and associated morbidity have been largely unsuccessful. The pancreaticoenteric anastomosis post pancreaticoduodenectomy in a high-risk pancreas represents a significant surgical and clinical challenge. In this narrative review, we present the strategies for early identification and comprehensive management of the high-risk pancreas as per the available literature and present a stepwise algorithmic approach of different fistula mitigation strategies in patients undergoing pancreaticoduodenectomy. Medline, PubMed, Embase, Cochrane Library, and various center-specific guidelines were searched for the pancreas, pancreatic cancer, pancreatectomy, pancreatoduodenectomy, Whipple's operation, postoperative, complications, fistula, High-risk pancreas, risk assessment, different predictors, and scoring systems for the high-risk pancreas, current and emerging concepts in the development of POPF and mitigation strategies management and treatment in various combinations. Over the years, literature has mainly addressed the technical aspects of pancreatico-enteric anastomosis; however, the impact of different technical modifications has been at the most elusive. Recent literature has focused on other aspects like remnant ischemia, locoregional inflammation, and postoperative acute pancreatitis among others, defining their evolving role in pathophysiology of POPF. Although many pre-operative risk prediction models are available; their intra-operative implications are not clear. Furthermore, the evidence available on the mitigation strategies is limited, heterogeneous, and center specific. Fistula prediction includes numerous potentiating factors in addition to the factors described in various Fistula Risk Scores. Early identification of these high-risk scenarios allows the algorithmic application of mitigation strategies. Management of the high-risk pancreas starts in the pre-operative period by early identifications of the risk factors and then continues into the intra-operative period with strategies to decrease intraoperative blood loss, precise anastomosis, and external stenting wherever feasible; goal-directed fluid therapy as well as total pancreatectomy (TP) in certain highly selected scenarios followed by early identification of complications in the postoperative period and appropriate and early management of the same. The coherent application of these mitigation strategies provides the opportunity for the best possible outcome in this complicated scenario. At present, the zero post-operative pancreatic fistulae seem unattainable, and time has come to study the strategies outside the operation theatre. Till preventive strategies become mainstream, a strategic personalized algorithmic approach may yield best outcomes.