Pancreatic cancer (PaC) is the fifth leading cause of cancer death in the world, but the molecular mechanisms for its development remain unclear. Regenerating islet-derived protein 3-alpha (Reg3A) has been reported overexpressed in pancreatic inflammation and associated with PaC malignancies, thus believed as a potential target in inflammation-linked pancreatic carcinogenesis. Silencing of suppressor of cytokine signaling SOCS3, a well-known feedback inhibitor of cell proliferation, has been found in many human cancers. Here, we identified that SOCS3 was aberrantly methylated in its CpG island in 3/5 human PaC cell lines and 11/36 cancer tissue samples. SOCS3 restoration by a demethylating agent, 5-aza-2'-deoxycytidine, remarkably suppressed cell proliferation and induced apoptosis of methylated PaC cells. Moreover, we also have shown that Reg3A was highly expressed in PaC cells and tissue samples. Assessment of potential relationship between SOCS3 and Reg3A aberrations in vitro revealed that SOCS3 worked downstream of Reg3A and modulated Reg3A-linked pro-tumor functions. siRNA-mediated SOCS3 knock-down in normal pancreatic epithelial cells and plasmid-transfected SOCS3 overexpression in PaC cells, respectively, resulted in the obvious promotion and inhibition of Reg3A-induced cell proliferation, thereby suggesting SOCS3 negatively regulating Reg3A-mediated PaC progression. In addition, our findings also revealed that JAK/STAT3/NF-κB appear involved in the effect of SOCS3-Reg3A interaction on pancreatic cell growth. In summary, SOCS3 inactivation by methylation was demonstrated to act in synergy with Reg3A overexpression to promote PaC cell growth and maybe the progress of inflammation-linked pancreatic carcinogenesis. Reg3A overexpression promoted cell growth in pancreatic cancer. SOCS3 is a key target in cancer by inhibiting cell growth and inducing apoptosis. SOCS3 negatively regulated Reg3A-mediated cell growth in pancreatic cancer. SOCS3 methylation act in synergy with Reg3A overexpression to promote pancreatic cancer cell growth.