Background & Aims: Perturbations in pancreatic ductal bicarbonate secretion often result in chronic pancreatitis. Although the physiological mechanism of ductal secretion is known, its transcriptional control is not well characterized. Here, we investigate the role of the transcription factor Hematopoietically-expressed homeobox protein (Hhex) in pancreatic secretion and pancreatitis. Methods: We derived mice with pancreas-specific, Cre-mediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histological and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells (PDCs) were isolated to discover differentially expressed transcripts upon acute Hhex ablation on a cell autonomous level. Results: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia in young mice did not result from perturbations of Hnf6, Hnf1beta, or primary cilia expression. RNA-seq analysis of Hhex-ablated PDCs indicated the G-protein coupled receptor Natriuretic peptide receptor 3 (Npr3), implicated in paracrine signaling, was upregulated 4.70-fold. Conclusions: Although Hhex is dispensable for ductal cell function in the adult, ablation of Hhex in pancreatic progenitors results in pancreatitis. Our data highlight the critical role of Hhex in maintaining ductal homeostasis in early life and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis.