Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas, but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor PRDM3 is expressed at low levels in normal pancreatic acini, and its expression increases during tumorigenesis. Although PRDM3 promotes the proliferation and migration of PDAC cell lines, the role of PRDM3 during PDAC initiation, progression and metastasis is unclear. In this study, we showed that high levels of PRDM3 expression in the human pancreas were associated with pancreatitis and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (PtflaCreER; Prdm3flox/flox mice) in the context of oncogenic Kras expression and supraphysiological caerulein injections, respectively. Prdm3 deficiency promoted acinar-to-ductal cell reprogramming in both caerulein-induced pancreatitis and KrasG12D-driven preneoplastic lesion formation. To our surprise, PRDM3 knockout significantly suppressed cell migration and invasion in pancreatic cancer cell lines. These results indicate that PRDM3 plays an important role in maintaining pancreatic acinar cell status but have different functions in pancreatic cancer cells. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon caerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout normal acini and cancer cell lines revealed that pathways involved in the inflammatory response were significantly upregulated. Taken together, our results suggest that Prdm3 promotes the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation and thus plays previously unexpected suppressive role during PDAC initiation.