The relationship between diabetes mellitus and pancreatic cancer is complex. Diabetes has been postulated to be both an independent risk factor and a consequence of pancreatic cancer. Our previous study confirmed that curcumin plays a vital role in inhibiting the epithelial-mesenchymal transition of pancreatic cancer cells. However, whether curcumin attenuates hyperglycemia-induced cancer invasive and migratory abilities and the underlying mechanisms are not yet well understood. As high glucose is able to induce the expression of epidermal growth factor (EGF), which is intimately related with tumor progression, the aim of this study was to evaluate whether curcumin could influence the high glucose-induced EGF/EGFR pathway and the biological activity of pancreatic cancer cells. Human pancreatic cancer BxPC-3 cells were exposed to high glucose or EGF, with or without curcumin, LY 294002 (an Akt inhibitor) or PD 98059 (an ERK inhibitor). MTT, Transwell invasion and wound healing assays were used to detect the proliferation, invasion and migration potential of cancer cells. The activation of p-EGFR, p-ERK and p-Akt was determined by western blot analysis. The expression levels of uPA and E-cadherin were examined using qRT-PCR and western blot analysis. The results showed that high glucose could not only promote the proliferation, invasion and migration of pancreatic cancer cells, but also induce the expression of EGF and activation of EGFR, ERK and Akt. These effects of high glucose were counter-balanced by curcumin. EGF-induced proliferative, invasive and migratory abilities of BxPC-3 cells were abrogated by curcumin, LY 294002 and PD 98059. In addition, EGF-modulated activation of EGFR, ERK and Akt, as well as the expression of uPA and E-cadherin were inhibited by curcumin. Taken together, the present study indicates that curcumin suppresses hyperglycemia-driven EGF-induced invasion and migration of pancreatic cancer cells by inhibiting the EGF/EGFR signaling pathway and its downstream signaling molecules including ERK and Akt. Curcumin is a potential anticancer agent for pancreatic cancer.