Bangia fusco-purpurea polysaccharide (UBFP) with ultra-high pressure assisted extraction has good in vitro hypolipidemic activity. To be explored as a natural hypolipidemic agent, the alleviation effect of UBFP on in vivo dyslipidemia in high-fat diet (HFD) induced mice was further investigated. Compared with native polysaccharide (BFP), UBFP was better to reduce weight gain, fat accumulation, serum and hepatic lipid abnormalities for HFD induced mice. This might be caused by the factor that UBFP was more effective to improve the diversity and structure of gut microbiota especially with SCFAs-producing bacteria (e.g., Allprevotella and Akkermansia) increased. Moreover, UBFP could up-regulate tryptophan, 5-hydroxyindoleacetic acid, leptin and N-arachidonic acid glutamate levels, and exhibited significant differential enrichment in the pathways of lysine biosynthesis, arginine biosynthesis, and tryptophan metabolism. In addition, UBFP could regulate energy metabolism and enhance fatty acid oxidation by inhibiting PPARγ protein expression and activating AMPK and ACC signaling pathways. Overall, with ultra-high pressure assisted extraction, UBFP possessed better function of regulating lipid homeostasis, which resulted from the altered structure of polysaccharides, improved intestinal flora and metabolites. The findings can lay the theoretical foundation for the design and development of desirable polysaccharides on regulating lipid homeostasis through ultra-high pressure modification.