Altered O-glycosylation is a key contributor to various pathophysiological processes. Notably, the expression of the Tn antigen is primarily attributed to dysfunction of the chaperone Cosmc, while the overexpression of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) has also been implicated in numerous diseases. We generated a transgenic mouse model with conditional Cosmc-knockout and simultaneous overexpression of polypeptide N-acetylgalactosaminyltransferase 2 (GalNT2) mediated by the pancreas-specific transcription factor 1a (Ptf1a)-Cre mouse strain to investigate the effect of Tn antigen overexpression on the pancreas in vivo. Histopathological examination of the transgenic pancreas revealed a chronic pancreatitis phenotype with interlobular fibrosis and focal necrosis after only a few weeks as a result of Tn antigen overexpression. In the later stages, there was a progressive loss of pancreatic parenchyma with consecutive exocrine pancreatic insufficiency and malnutrition in the transgenic mice. Flow cytometric analyses have also confirmed that significant infiltration of immune cells occurs in the course of pancreatitis. In the transgenic mouse model presented here, we demonstrated that overexpression of the Tn antigen in the pancreas results in chronic pancreatitis, highlighting the pathophysiological importance of truncated O-glycosylation.