Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism under conditions of stress such as starvation, obesity and hypothermia. Rapid induction of FGF21 is also observed in experimental models of pancreatitis, and FGF21 reduces tissue damage observed in these models, suggesting a non-metabolic function. Pancreatitis is a debilitating disease with significant morbidity that greatly increases the risk of pancreatic ductal adenocarcinoma. The goals of this study were to examine the regulation and function of FGF21 in acinar cell injury, specifically in a mouse model of pancreatic injury (Mist1^-/-). Mist1^-/- mice exhibit acinar cell disorganization, decreased acinar cell communication and exocytosis, and increased sensitivity to cerulein-induced pancreatitis (CIP). Examination of Fgf21 expression in Mist1^-/- mice by qRT-PCR, Northern blot, and Western blot analysis showed a marked decrease in pancreatic Fgf21 expression before and after induction of CIP compared to C57Bl/6 mice. To determine if the loss of FGF21 accounted for the Mist1^-/- phenotypes, we generated Mist1^-/- mice over-expressing human FGF21 from the ApoE promoter (Mist1^-/-ApoE-FGF21). Re-expression of FGF21 partially mitigated pancreatic damage in Mist1^-/- tissue based on reduced intrapancreatic enzyme activation, reduced expression of genes involved in fibrosis, and restored cell-cell junctions. Interestingly, alteration of Fgf21 expression in Mist1^-/- tissue was not simply due to a loss of direct transcriptional regulation by MIST1. Chromatin immunopreciptation indicated that the loss of Fgf21 in the Mist1^-/- pancreas is due, in part, to epigenetic silencing. Thus, our studies identify a new role for FGF21 in reducing acinar cell injury, and uncover a novel mechanism for regulating Fgf21 gene expression.