Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial–mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells.