Pancreatic ductal adenocarcinoma (PDAC) is to become the second leading cause of cancer-related death by 2040. Many factors contribute to this dilemma, including lymphatic metastasis, which is the primary cause of PDAC metastasis. The inhibition of early lymph node metastasis, including the lymphangiogenic process, may be a novel strategy for PDAC treatment. Through miRNA sequencing of plasma extracellular vesicles (EVs) from PDAC patients, for the first time, we identified that plasma EV-miR-205-5p served as a non-invasive biomarker distinguishing lymphatic metastasis status (N0 vs. N2) in PDAC patients. Using tissue microarray and in situ hybridization, we discovered that miR-205-5p was highly expressed in PDAC, but negatively correlated with lymph node metastasis. By in vivo and in vitro experiments, we demonstrated its unique mechanism of action via EV-mediated transfer to human lymphatic endothelial cells (HLECs), leading to systematic downregulation of VEGFA and inhibition of the Akt/Erk pathway, which suppressed lymphangiogenesis. Delivering miR-205-5p via engineered EVs might be a promising strategy to eliminate PDAC lymphatic metastasis and improve prognosis.