Nuclear factor E2-associated factor 2 (Nrf2)/Antioxidant Response Element (ARE) signaling pathway is an endogenous antioxidant pathway that protects cells from oxidative damage. This pathway is triggered when aquatic organisms are exposed to environmental toxicants. In this study, CpMafK (musculoaponeurotic fibrosarcoma K of Cristaria plicata) mRNA expression in hepatopancreas and gills were up regulated after Cristaria plicata (C. plicata) was exposed to microcystin (MC), which showed that CpMafK protected C. plicata from MC. After MC treatment and CpNrf2 (Nrf2 of Cristaria plicata) knockdown, the mRNA expression of CpMafK was down regulated. After MC treatment and CpMafK knockdown, the mRNA expression of CpNrf2 was down regulated. Indicating that the expression of CpNrf2 was positively correlated with CpMafK. CpGPx (GPx of Cristaria plicata) mRNA was also down regulated with the down regulation of CpMafK and CpNrf2. CpGPx promoter contains a variety of transcription factor binding sites, including Nrf2, ARE elements, etc. Gel blocking experiments showed that CpNrf2/CpMafK heterodimers were bound to CpGPx promoters in vitro. Dual luciferase reporter assay showed that CpNrf2/CpMafK heterodimer negatively regulated CpGPx promoter in cells. In conclusion, Nrf2 and MafK mediate regulation of GPx play a crucial role in protecting bivalves from MC.