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Coxsackievirus B3 (CVB3), a member of <i>Picornaviridae</i> family, is an important human pathogen that causes a wide range of diseases, including myocarditis, pancreatitis, and meningitis. Although CVB3 has been well demonstrated to target murine neural progenitor cells (NPCs), gene expression profiles of CVB3-infected human NPCs (hNPCs) has not been fully explored. To characterize the molecular signatures and complexity of CVB3-mediated host cellular responses in hNPCs, we performed QuantSeq 3&#8242; mRNA sequencing. Increased expression levels of viral RNA sensors (<i>RIG-I</i>, <i>MDA5</i>) and interferon-stimulated genes, such as <i>IFN-&#946;</i>, <i>IP-10</i>, <i>ISG15</i>, <i>OAS1</i>, <i>OAS2</i>, <i>Mx2</i>, were detected in response to CVB3 infection, while <i>IFN-&#947;</i> expression level was significantly downregulated in hNPCs. Consistent with the gene expression profile, CVB3 infection led to enhanced secretion of inflammatory cytokines and chemokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). Furthermore, we show that type I interferon (IFN) treatment in hNPCs leads to significant attenuation of CVB3 RNA copy numbers, whereas, type II IFN (IFN-&#947;) treatment enhances CVB3 replication and upregulates suppressor of cytokine signaling 1/3 (SOCS) expression levels. Taken together, our results demonstrate the distinct molecular patterns of cellular responses to CVB3 infection in hNPCs and the pro-viral function of IFN-&#947; via the modulation of SOCS expression.