Pancreatitis is a debilitating inflammatory condition of the pancreas that can progress to severe systemic illness with multiorgan system failure, yet there are no targeted therapies available. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of inflammation, with miR-146a recognized for its anti-inflammatory properties. Our research reveals that miR-146a is markedly downregulated in both human pancreatic tissues and experimental models of pancreatitis. Using the cerulein-induced and L-Arginine-induced preclinical models of pancreatitis, severe pancreatitis was significantly exacerbated in miR-146a knockout mice compared to wild-type controls, characterized by increased pancreatic inflammation, edema, immune cell infiltration and necrosis, highlighting the protective function of endogenous miR-146a during disease progression. Furthermore, a single intravenous administration of a miR-146a mimic ameliorated pancreatic pathology, reducing tissue damage and inflammatory markers. In addition, treatment of human pancreatic organoids in vitro with cerulein or L-arginine induced inflammatory cytokine production, while co-treatment with the miR-146a mimic significantly suppressed the expression of key inflammatory cytokines including interleukin-6 (IL-6) and IL-1β, compared to scrambled miRNA control. Mechanistically, our data reveals that miR146a modulates inflammasome activities in pancreatic tissues, reducing the activation of caspase-1 and the release of mature IL-1 β. Together, these findings strongly support the role of miR-146a as a central modulator of pancreatic inflammation and present compelling evidence that therapeutic delivery of miR-146a mimics could represent a novel, targeted strategy to treat pancreatitis. This work advances our understanding of miRNA-mediated regulation in pancreatic inflammation and paves the way for translational research aimed at developing miRNA-based interventions for inflammatory pancreatic diseases.