Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, primarily due to its rapid acquisition of drug resistance and the complex tumor microenvironment. Conventional cancer therapies, including chemotherapy and radiotherapy, often fail to elicit durable responses because PDAC cells exhibit both intrinsic and extrinsic resistance, in which the intrinsic resistance is driven by genetic mutations, epigenetic alterations, overexpression of efflux transporters, and the presence of cancer stem cells while the extrinsic resistance is mediated by a dense desmoplastic stroma, hypovascularity, and immunosuppressive cellular components. This review comprehensively analyzes these multifactorial resistance mechanisms and examines cutting-edge nanotechnology-based strategies designed to circumvent them. We discuss the design of intelligent, stimuli-responsive nanocarriers, including pH-sensitive, redox-sensitive, and enzyme-activated systems that enable spatiotemporally controlled drug release, thereby enhancing drug accumulation within tumor cells while minimizing systemic toxicity. Additionally, advances in surface functionalization and active targeting strategies, such as the use of ligand-conjugated nanoparticles, are highlighted for their role in enhancing selective delivery to both the bulk tumor cells and therapy-resistant cancer stem cell populations. Mechanistic insights are provided into how these nanomedicine interventions bypass traditional resistance pathways by facilitating intracellular drug delivery, co-delivering combination therapies, and modulating the tumor microenvironment to enhance therapeutic efficacy. These innovative strategies offer promising avenues to overcome drug resistance in PDAC, potentially transforming therapeutic outcomes for this aggressive disease.