Pancreatic cancer is a major contributor to the cancer-related mortality rate. The lack of prominent biomarkers is one of the major limitations in the early diagnosis of pancreatic ductal adenocarcinoma (PDAC). Next-generation sequencing (NGS) has led to a major transformation in the field of oncology by easing the process of data collection, pipeline analysis, data interpretation and cost-effectiveness. NGS, high-throughput screening detection and identification of prognostic markers such as KRAS, SMAD4, TP53, CDKN2A and somatic mutations have been the game-changer in the field of Clinical Oncology which can allow early detection, personalised treatment and progressive therapy programs in PDAC. The current review gives an overview of NGS technology and its advancement in understanding the genetics of pancreatic cancer. The unique features of somatic mutation in PDAC, various case studies and different tools to help choose appropriate pipeline for specific analysis, clinical applications, their limitations and future aspects have been highlighted.