Cancer is a life-threatening disease, and the occurrence of metastasis, which increases the lethality of primary tumors, is increasing. The epithelial-to-mesenchymal transition (EMT) is a biological process by which epithelial cells lose cell-cell adhesion properties and acquire mesenchymal properties, including motility and invasiveness. EMT is considered an early stage of metastasis; therefore, inhibiting EMT may be an effective anticancer therapy. In the present study, the antimetastatic effect of piperlongumine (PL) was assessed in human cancer cells. PL is a single component isolated from long pepper (Piper longum) and it has been studied for its antibacterial, antiangiogenic, and antidiabetic activities. Migration assays (wound healing assay) and transwell invasion assays showed that PL inhibited the migration and invasion of cancer cells. Western blotting and immunofluorescence imaging showed that TGF-β upregulated the transcription factors Snail1 and Twist1 and downregulated E-cadherin, a marker of epithelial cells, inducing EMT. PL might inhibit TGF-β-induced EMT by downregulating Snail1 and Twist1 and upregulating E-cadherin in cancer cells. In summary, PL might inhibit TGF-β-induced EMT, suggesting that it is a promising anticancer agent.