The Nyctereutes procyonoides is highly regarded in the farming and leather industries because of the high value of its fur, which renders artificial feeding a crucial aspect. However, high-fat diets have always been associated with a variety of digestive disorders. This study aimed to investigate the impact of high-fat diets on the gut microbiota and the mechanisms of gut damage in Nyctereutes procyonoides. 16S rRNA sequencing demonstrated that high-fat diets caused diarrhea and intestinal damage through alterations in the gut microbiota: a decrease in the abundance of Firmicutes, an increase in the abundance of Proteobacteria and Actinobacteria, and an increase in the abundance of Enterococcaceae, Escherichia coli-Shigella, Clostridium and Lactobacillus. Subsequently, changes in metabolic pathways, such as amino and fatty acid pathways, were identified by KEGG and COG enrichment analysis, and the TLR4/NF-κB/NLRP3 inflammatory signaling pathway was shown to be activated by high-fat diets. In addition, high-fat diets lead to the accumulation of ROS and MDA and reduce the activity of the antioxidant enzymes GSH-PX and SOD. Correspondingly, the levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α) were significantly increased, and the apoptosis and necrosis signaling pathways of colonic cells were detected, causing a dramatic decrease in the expression of intestinal tight junction proteins (Occludin, E-cadherin, ZO-1 and ZO-2). In conclusion, high-fat diets altered the structure of the Nyctereutes procyonoides gut microbiota community and led to colon damage. This study provides new insights into the intestinal health of Nyctereutes procyonoides.Graphical