Objective: Pancreatic ductal adenocarcinoma (PDAC) is a disease with high mortality. Many so-called “junk” noncoding RNAs need to be discovered in PDAC. The purpose of this study was therefore to investigate the function and regulatory mechanism of the long noncoding RNA MEG3 in PDAC. Methods:The Gene Expression Omnibus database (GEO database) was used to determine the differential expression of long noncoding RNAs in PDAC, and MEG3 was selected for subsequent verification. Tissue and cell samples were used to verify MEG3 expression, followed by functional detectionin vitro andin vivo. Microarrays were used to characterize long noncoding RNA and mRNA expression profiles. Competing endogenous RNA analyses were used to detect differential MEG3 and relational miRNA expression in PDAC. Finally, promoter analyses were conducted to explain the downregulation of MEG3 PDAC. Results: We generated a catalogue of PDAC-associated long noncoding RNAs in the GEO database. The ectopic expression of MEG3 inhibited PDAC growth and metastasisin vitro andin vivo, which was statistically significant (P< 0.05). Microarray analysis showed that multiple microRNAs interacted with MEG3. We also showed that MEG3, as a competing endogenous RNA, directly sponged miR-374a-5p to regulate PTEN expression. The transcription factor, Sp1, recruited EZH2 and HDAC3 to the promoter and transcriptionally repressed MEG3 expression. Finally, clinical data showed that MEG3 and miR-374a-5p expressions were correlated with clinicopathological features. Statistically, Sp1, EZH2, HDAC3, and miR-374a-5p were negatively correlated with MEG3 (P< 0.05). Conclusions:Reduced MEG3 levels played a crucial role in the PDAC malignant phenotype, which provided insight into novel and effective molecular targets of MEG3 for pancreatic cancer treatment.