Both miR-21 and miR-183 are upregulated in hepatocellular carcinoma (HCC) and are considered as oncomiR. However, their oncogenic roles are still not fully understood. This study aimed to explore the regulative role of miR-21 and miR-183 over suppressors of cytokine signaling 6 (SOCS6), a negative regulator of cytokine receptor signaling. qRT-PCR analysis was performed to assess miR-21 and miR-183 expression in tumor tissues obtained from HCC patients and in HCC cell lines HepG2 and Hep3B. Their regulation over SOCS6 is verified using dual luciferase assay and Western blot analysis. The function of miR-21/miR-183-SOCS6 axis in cell growth, invasion and apoptosis was studied. MiR-21 and miR-183 expression in HCC tissues than in adjacent normal tissues. Knockdown of miR-21 and miR-183 in HepG2 and Hep3B cells could decrease cell viability, increase cell apoptosis and decrease cell invasion. Based on the dual luciferase assay and Western blot analysis, we confirmed that both miR-21 and miR-183 can simultaneously target SOCS6 and modulate its expression at protein level. Overexpression of SOCS6 without 3'UTR could significantly lower cell growth rate and invasion capability, but increase relative caspase 3/7 activity and the ratio of apoptotic cells. However, these effects could not be blocked by miR-21 or miR-183 mimics. This study revealed a novel miR-21/miR-183-SOCS6 axis that might play an important role in modulating cell growth and invasion of HCC cells.