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Coxsackievirus B4 (CV-B4) can infect human and murine thymic epithelial cells (TECs). In a murine TEC cell line, CV-B4 can downregulate the transcription of the insulin-like growth factor 2 (<i>Igf2</i>) gene coding for the self-peptide of the insulin family. In this study, we show that CV-B4 infections of a murine TEC cell line decreased <i>Igf2</i> P3 promoter activity by targeting a region near the transcription start site; however, the stability of <i>Igf2</i> transcripts remained unchanged, indicating a regulation of <i>Igf2</i> transcription. Furthermore, CV-B4 infections decreased STAT3 phosphorylation in vitro. We also showed that mice infected with CV-B4 had an altered expression of <i>Igf2</i> isoforms as detected in TECs, followed by a decrease in the pro-IGF2 precursor in the thymus. Our study sheds new light on the intrathymic regulation of <i>Igf2</i> transcription during CV-B4 infections and supports the hypothesis that a viral infection can disrupt central self-tolerance to insulin by decreasing <i>Igf2</i> transcription in the thymic epithelium.