In this study, the effects of Stichopus japonicus acid mucopolysaccharide (SJAMP) on the apoptosis of the human hepatocellular carcinoma cell line HepG2 were examined. The underlying mechanism was investigated by determining the effect of SJAMP on the expression of Bcl-2 and nm23-H1 genes in HepG2 cells. In vitro cultured HepG2 cells were treated with different concentrations of SJAMP. The dimethylthiazol (MTT) assay was used to determine the inhibition of cell proliferation. Expression of Bcl-2 and nm23-H1 genes was determined by Western blot analysis. The results showed that SJAMP inhibited the proliferation of HepG2 cells in a time- and dose-dependent manner, SJAMP induced apoptosis in HepG2 cells, and SJAMP decreased the expression of Bcl-2 and increased the expression of nm23-H1. We conclude that SJAMP inhibits the proliferation of HepG2 cells by inducing apoptosis. These results provide a theoretical basis for the utilization of SJAMP as a potential antitumor component for the treatment of hepatocellular carcinoma.