Human immediate early response 2 (IER2) has been implicated in tumor cell motility and metastasis; however, the underlying mechanisms in hepatocellular carcinoma (HCC) metastasis remain to be clarified. In this study, we demonstrate that dysregulation of IER2 was shown in HCC clinical samples, and IER2 expression resulted in the promotion of cell migration and invasion in vitro, and HCC tumor growth and pulmonary metastasis in vivo. Moreover, we showed that IER2 expression altered assembly of the actin cytoskeleton rearrangement. Furthermore, MAPK and PI3K/Akt signaling pathways induced by IER2 were confirmed to be probably involved in regulating the activity of Rho GTPases, such as RhoA, Rac1 and Cdc42. Collectively, our results indicated a significant role of IER2 in the HCC cell motility and metastasis through MAPK and PI3K/Akt signaling pathways to regulate the activity of Rho GTPases, thereby modulating actin cytoskeleton rearrangement, unveiling a novel mechanism of cell motility regulation induced by IER2.