Recent studies focus on long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In pancreatic cancer, several lncRNAs have been mentioned as important actors in tumorigenesis. However, the function of lncRNA ANRIL (named as ANRIL as follows) in pancreatic cancer has not been elucidated. In the present study, we show that ANRIL was up-regulated while miR-181a was down-regulated in pancreatic cancer tissues and HMGB1 was highly expressed. Knockdown of ANRIL in pancreatic cancer repressed cellular proliferation, invasion, migration, and reduced chemotherapy resistance to gemcitabine. ANRIL was negatively correlated with miR-181a, while overexpression of miR-181a could reverse the effect. For further mechanism research, we found that miR-181a aimed to HMGB1 which activated cell autophagy. Taken together, our results implicate that the ANRIL, by targeting miR-181a, activates the HMGB1-induced cell autophagy, which is thought to be critical for oncogenesis.