Purpose: The biological functions of neuropilin and tolloid-like 2 ( NETO2 ) in the progression of pancreatic cancer remained unexplored. We aimed to investigate the biological roles and underlying molecular mechanisms of NETO2 in pancreatic cancer. Materials and methods: Thirty paired pancreatic tumor tissue samples and corresponding nontumor tissues were obtained from 30 pancreatic cancer patients who did not receive preoperative chemotherapy or radiotherapy. The changes in multiple cellular functions associated with tumor progression were assessed after NETO2 knockdown/overexpression in pancreatic cancer cell lines. Additionally, a mouse-xenograft model was developed to verify the in vitro results. Results: NETO2 was upregulated in pancreatic tumor tissues. Elevated expression of NETO2 was not only associated with an advanced tumor stage, but was also a prediction of poor prognosis for pancreatic cancer patients. Knockdown of NETO2 in pancreatic cancer cell lines arrested the cell cycle and inhibited cell proliferation, colony formation, invasion, and migration; in contrast, overexpression of NETO2 had an opposite effect on all of these parameters. A STAT3 specific inhibitor, cryptotanshinone, reversed the tumor-promoting effects induced by NETO2 overexpression in pancreatic cancer. Western blot analysis showed that invasion and migration were closely related to epithelial–mesenchymal transition, and that the STAT3 signaling pathway was involved in NETO2 -mediated oncogenic transformation in pancreatic cancer cells. Furthermore, NETO2 knockdown significantly inhibited the growth of pancreatic tumor xenografts in nude mice. Conclusion: NETO2 has an important role in the progression and metastasis of pancreatic cancer and could serve as a novel candidate for targeted therapy of pancreatic cancer.