Epithelial-mesenchymal transition (EMT) plays an important role in tumor metastasis of human nonsmall cell lung cancer (NSCLC). The Wnt pathway is identified as a key regulator of normal tissue development, and its aberrant activation contributes to the process of EMT. The secreted frizzled-related protein 1 (sFRP1), a Wnt-signaling antagonist, is downregulated in many tumors, including lung cancer. However, the role of sFRP1 in EMT and tumor metastasis remains unclear. In this study, we found that sFRP1 was dramatically downregulated in transforming growth factor β1 (TGF-β1)-induced EMT in the A549 human lung cancer cell line. Restoration of sFRP1 could inhibit the TGF-β1-induced EMT phenotype and tumor metastasis of the A549 cell line both in vitro and in vivo through inhibition of the Wnt pathway. Furthermore, FH535, a reversible Wnt-signaling inhibitor, exerted a similar effect on the TGF-β1-induced EMT phenotype. These results indicate that sFRP1, an endogenous antagonist of the Wnt pathway, inhibits TGF-β1-induced EMT, and might be a potential biomarker for the treatment of NSCLC.