Neural precursor cell expressed, developmentally downregulated 9 (NEDD9), is a focal adhesion scaffold protein which has been associated with metastasis in several cancers. Recent study found that NEDD9 expression was upregulated in HCC. However, the precise function of NEDD9 in HCC is still unclear. In the present study, we demonstrated that high NEDD9 expression was associated with the invasiveness of HCC in clinical samples. Moreover, by gain-and-loss function studies, we revealed that silencing of NEDD9 expression inhibited cancer cells proliferation, migration and invasion, while upregulated expression of NEDD9 promoted invasion and metastasis of HCC cells in vitro and in vivo. Further studies revealed that NEDD9 inversely regulated E-cadherin in HCC cells and HCC tissues, which indicated that NEDD9 might promotes the invasion and metastasis of HCC cells through the downregulation of E-cadherin, possibly by inducing EMT. On the whole, our findings thus indicate that NEDD9 may serve as a metastasis-promoting gene and potential therapeutic target for the treatment of hepatocellular carcinoma.