Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Long non-coding microRNAs (lncRNAs) are a newly discovered type of regulatory molecule with both diagnostic and prognostic value, but the role of lncRNA in PDAC has not been well investigated until now. Here, we present evidence that shows that the lncRNA DGCR5 is significantly reduced in PDAC tissues as well as in PDAC cell lines and that the downregulation of DGCR5 predicts poor prognosis. Ectopic expression of DGCR5 inhibits the proliferation and migration, and promotes 5-FU resistances of PDAC cells. Further experiments demonstrated that DGCR5 and miR-320a regulate each other in a reciprocal manner and that DGCR5 reverses the inhibition of PDCD4 by miR-320a, which is involved in the regulation of the PDAC cell phenotype and response to 5-FU. Our findings provide novel information about the functions of lncRNAs in PDAC, some of which might be beneficial to the precise diagnosis, prognosis and individualized therapy of patients with PDAC in the future.