Cystatin 2 (CST2) is a protein coding gene that belongs to a large superfamily of cysteine protease inhibitors. The deregulation of CST2 has been implicated in human cancers. The role of CST2 in pancreatic carcinogenesis has not yet been investigated. In this study, Gene Expression Profiling Interactive Analysis was performed using the Cancer Genome Atlas (TCGA) dataset containing pancreatic tumor samples and normal tissues. The functional role of CST2 in pancreatic cells was investigated by gene knockdown in vitro and in mouse xenograft tumor model. We found that CST2 was overexpressed in pancreatic tumor samples and cell lines. The knockdown of CST2 led to reduced proliferation, migration, and invasion, while apoptotic events were increased upon CST2 silencing in pancreatic cancer cells. In the xenograft mouse model of pancreatic cells, CST2 knockdown also retarded tumor growth on tumor growth. RUNX1 was identified as a transcription factor which positively regulated the expression of CST2. Further, we showed that, CST2 knockdown suppressed the activation of the PI3K/AKT signaling in pancreatic cells. Overall, our findings suggest that CST2 serves as an oncogene which facilitates the progression of pancreatic cancer. RUNX1 functions to upregulate CST2 in pancreatic cancer cells and CST2 may promote the malignancy of pancreatic cells by maintaining the activation of PI3K/AKT signaling.