Signal transducer and activator of transcription 6 (STAT6) is activated by a Janus kinase (JAK) downstream of cytokine receptor signalling. This study describes the activation of STAT6 by viral nucleic acids. STAT6 was found to interact with STING (an adaptor protein involved in sensing nucleic acids) and the kinase TBK1 after infection with DNA viruses, and with STING, TBK1 and the adaptor protein MAVS after infection with RNA viruses. These interactions resulted in TBK1-dependent (but JAK-independent) STAT6 activation. Of note, the phosphorylation pattern of virus-activated STAT6 is different from that observed following cytokine stimulation. Moreover, STAT6 activation in response to viral nucleic acids upregulated the expression of CC-chemokine ligand 2 (CCL2), CCL20 and CCL26. Interestingly, STAT6-deficient mice had impaired survival following viral infection, suggesting that non-classical activation of STAT6 is crucial for antiviral immune responses.