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Pancreatic adenocarcinoma, a severe digestive malignancy, is characterized by its poor prognosis. The National Comprehensive Cancer Network (NCCN) persistently refines its guidelines, integrating cutting-edge evidence-based medical insights to standardize the diagnostic and therapeutic strategies of pancreatic adenocarcinoma. The NCCN clinical practice guidelines in oncology-pancreatic adenocarcinoma were updated twice on May 4 and June 19, 2023, respectively. Compared to the 2022 predecessor, these two updates placed a particular emphasis on immunotherapy/targeted therapy, the introduction of NALIRIFOX regimen, and supplementary treatment protocols for patients with intermediate performance status. This article provided an interpretation of the latest updates to the NCCN clinical practice guidelines in oncology-pancreatic adenocarcinoma, integrating relevant evidence-based medical findings.