Remodeling of cytoskeleton plays an important role in development of multiple cancers, including melanoma. As a group of F-actin regulators, the Ras homology (Rho) GTPase-activating proteins (ARHGAPs) were reported by accumulating studies as a set of significant mediators in cell morphology, proliferation, migration and invasion. To investigate the function of HMHA1 and its encode protein HA-1 in melanoma. The mRNA microarray was performed to screen the expression of ARHGAP family genes between melanoma tissues and nevi tissues. QRT-PCR and Western Blot were used to detect the expression of mRNA of HMHA1 and its relevant protein HA-1 respectively. Small interfering RNA was used to knock down the expression of HMHA1. Cell-count kit 8 assays and colony formation assays were used to evaluate the cell proliferative viability of melanoma cells. Flow cytometry was employed to analyze cell apoptosis. Transwell assay and the observation of cell morphology were used to evaluate the invasive and migrating activity of melanoma cells. In previous study, we first found that both the mRNA level of HMHA1and the expression of HA-1 were up-regulated in melanoma tissues and cell lines compared with nevi tissues and normal human melanocytes respectively. Blocking HMHA1 expression in melanoma cell lines WM35 and A375 suppressed their proliferation and function of colony forming. Moreover, silencing HMHA1 not only significantly increased cell apoptosis but also suppressed cell migration and invasion. Our results demonstrate that HMHA1 significantly promotes melanoma cells proliferation, invasion and migration, and prevents cell apoptosis. Additionally, it can be considered as a new diagnostic marker and drug target of melanoma.