Cutaneous air-breathing is one of the air-breathing patterns in bimodal respiration fishes, while little is known about its underlying formation mechanisms. Here, we first investigated the skin regeneration of loach (Misgurnus anguillicaudatus, a cutaneous air-breathing fish) and yellow catfish (Pelteobagrus fulvidraco, a water-breathing fish) through morphological and histological observations. Then, the original skins (OS: MOS, POS) and regenerated skins (RS: MRS, PRS) when their capillaries were the most abundant (the structural foundation of air-breathing in fish) during healing, of the two fish species were collected for high-throughput RNA-seq. A total of 56,054 unigenes and 53,731 unigenes were assembled in loach and yellow catfish, respectively. A total of 640 (460 up- and 180 down-regulated) and 4446 (2340 up- and 2106 down-regulated) differentially expressed genes (DEGs) were respectively observed in RS/OS of loach and yellow catfish. Subsequently, the two DEG datasets were clustered in GO, KOG and KEGG databases, and further analyzed by comparison and screening. Consequently, tens of genes and thirteen key pathways were targeted, indicating that these genes and pathways had strong ties to cutaneous skin air-breathing in loach. This study provides new insights into the formation mechanism of cutaneous air-breathing and also offers a substantial contribution to the gene expression profiles of skin regeneration in fish.