Hypermelanosis on the blind side is a major concern in tongue sole (Cynoglossus semilaevis) aquaculture in China and causes great economic loss for farmers. To investigate the relationship between DNA methylation and hypermelanosis, different skin tissues on both the ocular and blind sides of both normal and hypermelanotic fish were used in this study, and set analysis was utilized to narrow and filter the possible, potential, and direct differentially methylated regions (DMRs). A total of 2278, 1015, and 6740 DMRs were discovered, which belonged to 1786, 908, and 4210 genes, for possible, potential, and direct methylation types, respectively. Enrichment analysis revealed that the genes harboring DMRs associated with hypermelanosis were involved in the development of the skeletal system and embryonic organs during morphogenesis. Tens of key genes were mutually found by comparing methylation results with reported transcriptomic, ncRNA, and genetic studies. These results implied that hypermelanosis on the blind side in tongue sole is a complex trait that is affected by both genetic factors and environmental conditions and is regulated by a complicated gene network.