This study aimed to investigate the inhibitory effect of novel 3D-organocopper supramolecular coordination polymers (SCPs) on the invasive potential of HepG2 cells. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. The inhibitory effect of an SCP compound on the proliferation of HepG2 hepatoma cells was evaluated by cell vibility assay. DNA ladder bands were observed by DNA agarose gel electrophoresis. The influence of the SCP compound on phosphorylated ERK1/2, Bcl-2, and β-catenin protein expression of HepG2 cells was analyzed by Western blot. The SCP compound exerted an inhibitory effect on HepG2 cell proliferation in a dose-dependent manner. This inhibitory effect was confirmed by examination of cell morphology and DNA fragmentation. Furthermore, Western blot analysis revealed that phosphorylated ERK1/2 and β-catenin protein expression was inhibited after 24 h of treatment with the SCP compound, and that this event was associated with decreased Bcl-2 expression. We concluded that SCP can effectively inhibit the invasive potential of the ERK signaling pathway in HepG2 cells by altering apoptosis and by inhibiting Bcl-2 and β-catenin, which may play a significant role in this process.