Method A total of 270 juvenile M. salmoides with an initial body weight of (2.69±0.04) g were selected and randomly divided into 3 groups, with 3 replicates in each group. They were respectively fed with 3 types of isonitrogenous diets: control diet (CON group, 10% fat), high-fat diet (HFD group, 18% fat), and high-fat diet supplemented with sodium propionate (HFD+NaSP group, 18% fat+5 g/kg sodium propionate) for 56 days. The results showed that compared with the HFD group, the HFD+NaSP group exhibited significantly increased weight gain rate and specific growth rate. Serum triglyceride, total cholesterol content, as well as the activities of alanine aminotransferase and aspartate aminotransferase were significantly reduced in the HFD+NaSP group compared to the HFD group. The HFD+NaSP group demonstrated significantly elevated total antioxidant capacity, catalase, and superoxide dismutase activities, while malondialdehyde content was significantly reduced compared to the HFD group. Compared with the HFD group, the activities of intestinal lipase, amylase and pepsin in the HFD+NaSP group were significantly increased, the HFD+NaSP group showed significant upregulation of pparα and cpt1 expression in the liver, along with significant downregulation of srebp1, fas, acc tnf-α, il-1β, il-8 caspase3, caspase9, and bax expression. Regarding intestinal flora, the HFD+NaSP group displayed significantly higher Shannon and Simpson indices compared to the HFD group, while Ace and Chao indices showed no significant differences, the HFD+NaSP group significantly reduced the relative abundance of Mycoplasma while increasing Leifsonia abundance. In conclusion, dietary NaSP supplementation ameliorated the adverse effects of high-fat diet on the growth performance, liver health, and intestinal flora of M. salmoides. To provide theoretical references for promoting the application practice of sodium propionate in high-fat feed for fish.