SKP2 gene is an independent prognostic factor in some diseases and a potential oncogene. The molecular mechanism underlying the occurrence and development of hepatoma, and the involvement of the SKP2 in this process remain unclear. Here, in order to study the effect of SKP2 on proliferation, apoptosis and migration of hepatoma cells, we utilized lentivirus-mediated RNA interference technology using short hairpin RNAs (shRNAs) specific for SKP2. It was demonstrated that SKP2 expression was significantly upregulated in 809 hepatocarcinoma tissues compared to 379 normal liver tissues. The survival time of patients with high levels of SKP2 mRNA was shorter than those with low levels, and SKP2 expression was maximal in stage III hepatocellular carcinoma tissues. The effects of SKP2 silencing on proliferation, apoptosis, cell cycle, migration, and the expression of apoptosis proteins in Huh7 and HepG2 cells were evaluated by MTT assay, flow cytometry, colony formation assay, Transwell, and Western blot analysis. SKP2 expression was significantly reduced in stably transfected Huh7 and HepG2 cells, with knockout efficiencies of 95.7 and 85.8%, respectively. The viability, proliferation, and migration of transfected cancer cells were reduced. In these cells, the apoptosis rate was increased, and the cell cycle was arrested in the G2/M phase. The expression of the apoptosis-associated BCL-2/BAX proteins was decreased, while p53 was upregulated. Thus, we have shown that inhibiting the expression of SKP2 can significantly impede cancer cell proliferation and migration, halt the cell cycle, and induce apoptosis.