Decoy receptor 3 (DcR3), a decoy molecule belonging to the tumor necrosis factor receptor superfamily (TNFRSF), is a soluble receptor that can neutralize the biological effects of three other TNFSF members, namely, Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). DcR3 expression is increased in tumor cells. As such, DcR3 has been considered a potential biomarker to predict cancer invasion and progression of inflammation. However, the molecular mechanisms of DcR3 in tumor progression and metastasis remain poorly described. In the present study, DcR3 induced cytoskeleton remodeling, inhibited E-cadherin expression, and promoted cancer cell migration. Immunofluorescence and flow cytometry demonstrated that DcR3 expression was increased in hepatoma cells, whereas E-cadherin expression was significantly downregulated. Immunohistochemistry revealed that DcR3 and E-cadherin exhibited an opposite expression pattern between normal and cancerous liver tissues. Moreover, DcR3 treatment promoted IκBα degradation and p65 nuclear translocation. Therefore, the present study uncovered the mechanism underlying the function of DcR3 in cancer cell migration and provides evidence that DcR3 may be a potential target for cancer therapy.