Abstract: To study the effect and mechanism of walnut meal polyphenol extract on hyperuricemia (HUA), method of filling the corresponding mold making drug and walnut meal polyphenolic extract, a mouse model of hyperuricemia (HUA) was established by co-administration of 30 g/kg yeast paste by gavage (ig) and 300 mg/kg potassium oxonate by intraperitoneal injection (ip), and by the method of side-administration of the candidate and modeling drug. The serum uric acid (UA) and creatinine (Cr) of mice were detected, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) levels and xanthine oxidase (XOD), aspartate aminotransferase (AST) and alanine transaminase (ALT) activities in mice, hematoxylin-eosin staining of kidneys for observation and evaluation of pathology, LC-MS technique for liver metabolome, and Illumina technique for intestinal flora in mice. Results showed that, compared to the model group, renal index, serum UA, Cr, IL-6 levels and the activity of XOD, AST and ALT were significantly prevented from increasing in each subject group (P<0.0001 except P<0.05 of UA in low dose group). TNF-α levels were significantly prevented from increasing in the high and medium dose groups (P<0.01), and renal lesions and renal tubular vacuolization were reduced, and the abundance of the dominant intestinal Lactobacillus were increased. There were 20 differential metabolites including biomaker kynurenic acid and lysoPA, which mainly involved in regulating pathways such as TCA cycle, biosynthesis of siderophore group nonribosomal peptides, taurine and hypotaurine metabolism. In summary, the polyphenol extract from walnut meal can significantly prevent hyperuricemia. The mechanism may involve effectively reducing serum XOD activity, preventing the decrease in relative abundance of dominant Lactobacillus in the intestine of mice induced by modeling, regulating liver metabolism, effectively lowering lysoPA (P<0.05), and increasing kynurenic acid (P<0.05).