Pancreatic cancer is a devastating disease with a survival rate of less than 5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression. One of mechanisms enabling tumor cells to evade cellular stress and promote unhindered proliferation is the ER stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage but eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces unfolded protein response (UPR) by activating the PERK-eIF2α axis and the Ire1α-Xbp-1axis of unfolded protein response and leads to chronic ER stress in pancreatic cancer. Our results further show that GRP78, one of the major regulators of ER stress is downregulated by triptolide leading to cell death by apoptosis in MIA-PaCa2 cells and autophagy in S2-VP10 cells.