This study is to explore underlying mechanism of skin wound healing by snakehead fish soup using rat and cell models. We assessed skin wound changes after administering wild and farmed snakehead fish soup intragastrically, then using CCK-8 and scratch tests to evaluate cell proliferation and migration, last assessed vessel tubule formation by HUVEC cells. The results showed that the skin wound healing rates of rats after 14 days of intragastrical administration of farmed and wild snakehead fish soup were 52.71% and 57.76%, respectively, which were substantially greater than the control group (39.84%). With the administration of the soups, the collagen tissue on the skin wound was more homogenous and thicker, and type I collagen was denser. Additionally, interleukin-6 level in rat serum during wound healing was significantly lower, while cyclin-D1 and fibroblast growth factor-2 levels were higher. Furthermore, the soups (particularly at 50 μg/mL) significantly increased the proliferation and migration rates of both the HACAT and NIH3T3 cells, and considerably promoted the tubule formation of HUVEC cells. The findings confirm that the soup can promote skin wound healing and the underlying mechanism involves multiple roles including anti-inflammation, cell proliferation, vessel tubule formation, and collagen expression.