The induction of Smad signalling by the extracellular ligand TGF-β promotes tissue plasticity and cell migration in developmental and pathological contexts. Here, we show that vaccinia virus (VACV) stimulates the activity of Smad transcription factors and expression of TGF-β/Smad-responsive genes at the transcript and protein levels. Accordingly, infected cells share characteristics to those undergoing TGF-β/Smadmediated epithelial-to-mesenchymal transition (EMT). Depletion of the Smad4 protein, a common mediator of TGF-β signalling, results in an attenuation of viral cell-to-cell spread and reduced motility of infected cells. VACV induction of TGF-β/Smadresponsive gene expression does not require the TGF-β ligand or type I and type II TGF-β receptors, suggesting a novel, non-canonical Smad signalling pathway. Additionally, the spread of ectromelia virus, a related orthopoxvirus that does not activate a TGF-β/Smad response, is enhanced by the addition of exogenous TGF-β. Together, our results indicate that VACV orchestrates a TGF-β-like response via a unique activation mechanism to enhance cell migration and promote virus spread.