Hepatocellular carcinoma (HCC) is one of the most common human malignancies and also the leading cause of cancer-related death in the world. The mechanisms underlying the progression and metastasis of HCC remain unclear. The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbxw7) is broadly considered as a tumor suppressor gene. However, the role of Fbxw7 in HCC is not clear. To investigate the expression and biological functions of Fbxw7 in HCC, we examined Fbxw7 expression level using HCC tissue microarray and immunohistochemistry. Our data showed that Fbxw7 expression is significantly reduced in HCC compared with non-cancerous tissues (P<0.05). Fbxw7 levels were significantly associated with tumor differentiation (P=0.013), the incidence of portal or hepatic venous invasion (P=0.031), metastasis (P=0.027) and AJCC cancer stage (P=0.047). Then, we observed a strong correlation between low Fbxw7 expression and a worse 5-year survival of HCC patients (P<0.001). Furthermore, multivariate Cox regression analyses demonstrated that the Fbxw7 expression (P<0.001) was an independent factor for the prediction of the overall survival of HCC patients. We also found that both Fbxw7 mRNA and protein levels were significantly reduced in HCC cell lines compared with human liver non-tumor cell line. Moreover, our in vitro experiments showed a remarkable increase of cell migration and invasion in Fbxw7-knockdown cells and a decrease in Fbxw7-overexpress cells. In addition, the present study demonstrated that Fbxw7 is involved in the migration and invasion of HCC cells via regulating Notch1 and the downstream molecules of Notch1. Taken together, our findings indicate that Fbxw7 can be used as a prognostic marker; it has an important role in HCC progression and inhibits HCC cell migration and invasion through the Notch1 signaling pathway.