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In recent years, the global incidence of chronic kidney disease caused by popular high-protein diet is on the rise. As a traditional edible and medicinal fungus in Asian countries, Inonotus hispidushas been proved to have a variety of biological activities. In this study, a mouse model of chronic kidney disease was established, and the effect of Inonotus hispiduson chronic kidney disease induced by high protein diet was clarified by the comprehensive strategy of metabonomics and intestinal microbiota analysis. We found that Inonotus hispidusfermentation broth may alleviate renal damage by regulating glycerol phospholipid metabolism and bile acid metabolism, and its fermentation broth can reverse the intestinal microbiota imbalance caused by high-protein diet. In addition, through analysis, it is found that high-protein diet can down-regulate the level of Farnesoid X receptor in the kidney, resulting in lipid accumulation and a series of pathological changes in the kidney. We believe that Inonotus hispidushas the potential to become a new type of safe and effective functional food for the treatment of chronic kidney disease.