From our experimental results and our review of the literature, we propose the following conclusions: (1) Id-1 and CCN2 in HCC are associated with a malignant phenotype and poor prognosis in HCC; (2) enhanced stemness is profoundly influenced by the expression levels of Id-1 and CCN2; (3) CCN2 significantly activates the MAPK/Erk/Id-1 signaling pathway and Id-1 positive feedback amplified the expression of CCN2; (4) oxaliplatin combined with CCN2/MAPK/Erk signaling inhibition results in improved treatment effects in HCC. This evidence concerns the gene CCN2 and hepatocellular carcinoma.