Suppressor of cytokine signaling (SOCS) is a family of cytokine-inducible negative regulators of cytokine signaling and it plays a crucial role in various physiological processes. In the present study, the full-length cDNA of a SOCS (designated as EsSOCS6) was cloned from Chinese mitten crab Eriocheir sinensis. The open reading frame of EsSOCS6 cDNA was of 1266 bp, which encoded a polypeptide of 421 amino acid residues. There were two typically conserved SOCS family domains in EsSOCS6, including a central Src homology 2 (SH2) domain and a C-terminal SOCS box. The deduced amino acid sequence of EsSOCS6 shared 72–76% similarity with those of other SOCS6 family members. EsSOCS6 mRNA was constitutively expressed in all the examined tissues with higher expression levels in the immune-related tissues, such as hepatopancreas, hemocytes and gill. The mRNA expression levels of the EsSOCS6 in hemocytes were significantly up-regulated after the stimulations with lipopolysaccharide (LPS), Aeromonas hydrophila and polyinosinic-polycytidylic acid (poly (I:C)). The mRNA expressions of threonine/serine protein kinase (EsAkt) and EsRelish were dramatically declined after EsSOCS6 was interfered by dsRNA. Collectively, these results demonstrated that EsSOCS6 might regulate the activation of the NF-κB signaling pathway and play an important role in the innate immune responses of E. sinensis.