Salinity is a crucial environmental stress that severely affects fish growth and survival. Under environmental stress, DNA methylation plays an important role in gene expression and genome function. To better understand the epigenetic regulation mechanism of igf2 under low salinity stress, we analyzed the DNA methylation at 5’UTR, exon1, intron1, and exon2, and analyzed the relationship of DNA methylation with mRNA abundance as well as the special single CpG sites methylation patterns of igf2 in the liver of half smooth tongue sole under low salinity (15) for 0, 7, and 60 d. When exposed to low salinity, DNA methylation at 5’UTR and exon2 remained stable, while it was up-regulated firstly and then down-regulated at exon1 and intron1. Some single CpG sites of igf2 associated with low salinity, and most of these sites with significantly changed methylation levels ( P < 0.05) are located in intron1 area. The discrepant variation of single CpG sites methylation levels and igf2 expression further revealed that females and males showed different response to low salinity. Remarkably, the 38-CpG site of intron1 servers as a sexual marker. Additionally, our integrative analysis demonstrated that regional DNA of igf2 methylation had highly complex interplay on gene expression. The single CpG sites in intron1 were indispensable epigenetic markers under external environmental stress. Above all, to resist the low salinity stress, half smooth tongue sole liver can regulate the expression of igf2 through methylation of CpG sites in intron1.