LASP2 was recently demonstrated to serve as multifaceted roles in several types of cancers. However, its underlying mechanism in the progression of human liver cancer has not been explored. The aims of the current study were to detect LASP2 expression in a liver tissue microarray, and to determine whether LASP2 contributes to malignant phenotypes of HepG2 human hepatoblastoma cells. Our results revealed that LASP2 expression was downregulated in liver cancer tissues relative to normal non-cancerous tissues, and its downregulated expression was closely correlated with malignant process of liver cancer. In vitro, upregulation of LASP2 expression by transfection with LASP2 vector significantly suppressed HepG2 cells viability, colony formation and migration activities. Conversely, the viability, colony formation and migration abilities of HepG2 cells were increased when downregulating LASP2 expression by transfection with small interfering RNA targeting LASP2. Interaction study showed that silencing of LASP2 in HepG2 cells triggered high expression of Cyclin D1, ERK and p-ERK, and low expression of Bax, respectively. In addition, LASP2 silencing-induced malignant phenotypes were further attenuated after HepG2 cells treatment with ERK1/2 blocker PD98059. Collectively, our data suggest a link between LASP2 and MAPK/ERK axis in the development of hepatoblastoma and LASP2 may be a potential marker for assessment of liver cancer prognosis and staging.