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OBJECTIVE The aim of this study was to investigate the effects of eupatilin on protein kinase D1 (PKD1) and nuclear factor kappa B (NF-κB) signaling pathways in cerulein-induced in vitro pancreatitis. METHODS We used collagenase digestion to isolate pancreatic acinar cells from male C57BL/6 mice. In vitro acute pancreatitis was induced by treatment with a supramaximal dose of cerulein. Eupatilin was pretreated before stimulation with cerulein. RESULTS Eupatilin significantly reduced cerulein-induced amylase release in pancreatic acini. Eupatilin treatment downregulated cerulein-induced expression of interleukin (IL)-1β, IL-6, and CC chemokine ligands 2 and 5, but it upregulated expression of IL-4 and IL-10. We demonstrated that eupatilin pretreatment attenuated cerulein-induced necrosis in isolated pancreatic acinar cells. This effect of eupatilin was confirmed by lactic dehydrogenase assay, fluorescence-activated cell sorting analysis, and cytopathologic analysis. Eupatilin inhibited cerulein-induced activation of PKD1/NF-κB and the nuclear translocation of NF-κB. CONCLUSIONS Our data demonstrated that eupatilin is a potential therapeutic candidate for the treatment of pancreatitis through its ability to reduce cellular necrosis and inflammatory responses by inhibition of the PKD1/NF-κB signaling pathway.