TP-1 is a polysaccharide from one famous fungus Huaier. Treatment with TP-1 significantly inhibited the cell growth, adhesion, migration, and motility of SMMC-7721 cells in a dose-dependent manner. Real-time quantitative RT-PCR revealed a dose-dependent decrease in RNA-binding factor 1 (AUF-1) and astrocyte elevated gene-1 (AEG-1) messenger RNA (mRNA) levels in TP-1-treated SMMC-7721 cells, which is consistent with their protein expression detected by Western blotting. On the contrary, microRNA-122 (miR-122) expression increased in SMMC-7721 cells following TP-1 treatment. Moreover, TP-1 treatment at three doses apparently increased epithelial marker E-cadherin protein expression but decreased the mesenchymal marker N-cadherin protein level. In addition, the hematoxylin-eosin (H & E) staining showed that the TP-1 significantly inhibited the lung metastasis of liver cancer in mice orthotopic implanted with SMMC-7721 tumor tissue. Taken together, these findings proved the inhibitory effect of TP-1 on the growth and metastasis of SMMC-7721 cells, and TP-1 might be offered for future application as a powerful chemopreventive agent against hepatocellular carcinoma (HCC) metastasis.