Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide, and the highest incidence rates are reported in East Asia. We previously showed that SNAIL is upregulated in HCC tissues. In the present study, we aimed to investigate RNA interference-mediated targeting of SNAIL on the growth of HepG2 cells. We constructed three RNA interference plasmids targeting the SNAIL gene and selected the most efficient shRNA expression cassette. After the lentivirus (LV)-SNAIL small interfering (si)RNA vector was transfected into the HepG2 cell line, cell proliferation was measured using the MTT assay. E-cadherin mRNA and protein expression levels were examined by quantitative PCR and western blotting, respectively. We successfully constructed an LV-SNAIL siRNA lentiviral vector and demonstrated that it suppressed the expression of the SNAIL gene in HepG2 cells. RNA interference of SNAIL by the LV-SNAIL siRNA construct significantly inhibited the growth of HepG2 cells, in addition to significantly increasing E-cadherin mRNA and protein expression. Our findings strongly suggest that SNAIL and E-cadherin play a significant role in HCC progression, and exhibit a negative correlation. Furthermore, the expression of E-cadherin may be responsible for the reduced proliferation and survival of HepG2 cells. Thus, the SNAIL signaling pathway may provide a novel therapeutic target for the treatment of HCC.