Background: Type 2 diabetes is a well described extra-hepatic manifestation of hepatitis C virus (HCV) infection. This study aimed to explore the potential mechanism of KCNQ1 overlapping transcript 1 (KCNQ1OT1) in type 2 diabetes mellitus (T2DM) caused by HCV infection. Methods: Min6 cells were infected with HCV to establish a vitro model, and the HCV copy number was detected by real-time quantitative PCR (RT-qPCR). The mRNA and protein expressions of IL-10, IL 18, NLRP3, caspase-1, and GSDMD were analyzed by RT-qPCR and Western blot. Flow cytometry and TUNEL assay were used to evaluate the pyroptosis of cells and enzyme-linked immunosorbent assay (ELISA) detected the secretion of insulin. A dual luciferase reporter gene assay then verified the targeting relationship of KCNQ1OT1, miRNA-223-3p, and NLRP3. Results: KCNQ1OT1 was highly expressed in HCV-infected T2DM patients and HCV-infected 0-cells. Silencing KCNQ1OT1 inhibited 0-cell pyroptosis by regulating miR-223-3p/NLRP3, and inhibition of miR-223-3p or overexpression of NLRP3 reversed the pyroptosis by silencing KCNQ1OT1. Conclusions: Our findings indicate KCNQ1OT1 promotes HCV-infected 0-cell pyroptosis through the miRNA-223-3p/NLRP3 axis, effecting the production of insulin and accelerating the occurrence and development of T2DM.Regulating KCNQ1OT1 and its target genes will help to better understand the pathogenesis of T2DM induced by HCV infection and provide new theoretical foundations and therapeutic targets.