Pancreatitis is a life-threatening medical disorder that occurs when abnormally activated pancreatic enzymes damage surrounding pancreatic acinar cells, leading to the release of several pro-inflammatory cytokines. Subsequently, inflammation of the pancreas promotes the dedifferentiation of acinar cells towards a ductal-like, progenitor phenotype, to heal from pancreatic injury, in a process known as acinar to ductal metaplasia (ADM). Recent studies by our group suggest that the sialyltransferase, ST6Gal1 promotes ADM. ST6Gal1 adds sialic acid to N-glycosylated surface receptors and thereby regulates cell signaling and phenotype. In the current study, we report the novel finding that ST6Gal1 is upregulated in the pancreatic tissues of patients with chronic pancreatitis and mice with experimental pancreatitis, whereas ST6Gal1 expression is undetectable in normal acinar cells. These results are the first to show stark modulation of ST6Gal1 within pancreatic inflammation. While the upregulation of ST6Gal1 has been noted across multiple cancers, the mechanisms by which ST6Gal1 expression is modulated within an inflammatory milieu are not well understood. To evaluate inflammation-induced ST6Gal1 upregulation, we injected mice with cerulein to evoke pancreatitis. We first examined levels of pro-inflammatory cytokines through immunohistochemistry in cerulein-treated mice and observed striking increases in the release of both IL-6 and IL-1β. Accordingly, we proceeded to treat multiple pancreatic acinar cell line models with IL-6 and IL-1β to assess their respective capability to upregulate ST6Gal1. These two cytokines stimulated increases in ST6Gal1 mRNA and protein in all cell models. It's known that there are three major isoforms of ST6Gal1, each driven by a different promoter; thus, we investigated which of the three isoforms was increased following cytokine treatment. We found that the isoform driven by the P3 promoter, a ubiquitously expressed isoform known as "YZ", was the only isoform seen to be upregulated following cytokine treatment. To further understand the mechanisms by which IL-6 and IL-1β mediate their upregulation of ST6Gal1, we used an online transcription factor binding predictor to assess which transcription factors bind to the P3 promoter of the YZ isoform of ST6Gal1. On this P3 promoter, we found binding sites for STAT3, which is activated by IL-6, and NF-κB, which is activated by IL-1β. Furthermore, we observed STAT3 and NF-κB pathway activation following cytokine treatment. Importantly, STAT3 and NF-κB inhibitors blocked cytokine-induced ST6Gal1 upregulation in multiple cell models, thus confirming that IL-6 and IL-1β mediated their upregulation of the YZ isoform through the STAT3 and NF-κB pathways, respectively. Taken together, these results not only show ST6Gal1 modulation within pancreatitis but detail the mechanisms by which this occurs, thus providing significant insight into an area of research that has not been well characterized.