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Emerging evidence suggests a potential association between high selenium (Se) exposure and the development of type 2 diabetes mellitus (T2DM), a condition often associated with chronic low-grade inflammation. Pyroptosis, a form of programmed cell death characterized by the cleavage and activation of GSDMD by Caspases, has been implicated in T2DM. As an interferon regulatory factor, IRF2 plays a key role in regulating Caspase-GSDMD-mediated pyroptosis. However, the role of IRF2 in Se-induced islet cell pyroptosis and its contribution to T2DM development remain unclear. This study investigates the relationship between Se exposure and T2DM, focusing on the molecular mechanisms through which IRF2 mediates pyroptosis. Our findings show that Se accumulates in the serum of diabetic mice, exacerbating hyperglycemia, reducing serum insulin levels, and triggering pancreatic tissue atrophy and inflammation. Additionally, Se exposure leads to its accumulation in INS-1 cells, decreasing cell viability and impairing insulin secretion. Treatment with the pyroptosis inhibitor disulfiram (DSF) effectively suppressed Se-induced GSDMD expression, GSDMD-N cleavage, and the production of apoptosis-associated speck-like protein (ASC) and interleukins (IL)-18, confirming that Se exposure triggers pyroptosis in pancreatic islet cells. Both in vivo and in vitro experiments consistently demonstrate that Se exposure induces pyroptosis through activation of the IRF2/Caspase-4/GSDMD signaling pathway. Notably, lentivirus-mediated silencing of IRF2 significantly suppressed Se-induced pyroptosis. In conclusion, our study suggests that accumulated Se exposure promotes the progression of T2DM via the IRF2/Caspase-4/GSDMD-mediated pyroptosis pathway. Moreover, targeting IRF2 expression may effectively alleviate Se-induced pancreatic β-cell damage, providing a promising therapeutic target for the prevention and treatment of T2DM.