Hyperuricemia (HUA) is a vital risk factor for chronic kidney diseases (CKD) and development of functional foods capable of protecting CKD is of importance. This paper aimed to explore the amelioration effects and mechanism of Andrias davidianus bone peptides (ADBP) on HUA-induced kidney damage. In the present study, we generated the standard ADBP which contained high hydrophobic amino acid and low molecular peptide contents. In vitro results found that ADBP protected uric acid (UA)-induced HK-2 cells from damage by modulating urate transporters and antioxidant defense. In vivo results indicated that ADBP effectively ameliorated renal injury in HUA-induced CKD mice, evidenced by a remarkable decrease in serum UA, creatinine and blood urea nitrogen, improving kidney UA excretion, antioxidant defense and histological kidney deterioration. Metabolomic analysis highlighted 14 metabolites that could be selected as potential biomarkers and attributed to the amelioration effects of ADBP on CKD mice kidney dysfunction. Intriguingly, ADBP restored the gut microbiome homeostasis in CKD mice, especially with respect to the elevated helpful microbial abundance, and the decreased harmful bacterial abundance. This study demonstrated that ADBP displayed great nephroprotective effects, and has great promise as a food or functional food ingredient for the prevention and treatment of HUA-induced CKD.