Tbx3, a member of the T-box family of transcription factors, contributes directly to tumor formation, migration, and invasion. However, the role of Tbx3 in the metastasis of HCC remains unclear. In the present study, Tbx3 expression was detected in HCC tissues and cells by Western blot, and Tbx3 expression was regulated by use of siRNAs or lentivirus-mediated vectors. Here we found that Tbx3 protein expression increased in HCC tissues and cell lines. Tbx3 expression was positively associated with multiple tumor nodes, venous infiltration, and advanced TNM tumor stage. Survival analysis demonstrated that Tbx3 expression was an independent prognostic factor for HCC patients. In vitro assays further validated that Tbx3 indeed prompted HCC cell migration and invasion. In addition, Tbx3 expression was negatively related with E-cadherin expression in HCC tissues. Mechanically, Tbx3 inhibited the expression of E-cadherin, and then facilitated epithelial-mesenchymal transition (EMT) of HCC cells. Furthermore, the effect of Tbx3 knockdown on HCC cells was attenuated by E-cadherin knockdown. In conclusion, Tbx3 may be a novel prognostic factor, and it contributes to HCC cell migration, invasion, and EMT by repressing E-cadherin expression. Thus, Tbx3 may be recommended as a therapeutic target for HCC patients.