Objective To provide a pathological model for the screening and study of drugs for the treatment of hyperuricemic nephropathy by establishing a reasonable and stable mouse model with hyperuricemic kidney injury. Methods By administering one, two, or three of five drugs, oteracil potassium, hypoxanthine, adenine, ethambutol, and yeast extract, a model was established with hyperuricemia renal injury in KM mice, at different modeling times by using different modeling doses and modeling methods. The changes in serum uric acid, urea nitrogen, creatinine, liver xanthine oxidase (XOD), and adenosine deaminase (ADA) activity were determined, and the variations in weight of each group were analyzed. Results Compared with the normal group, the serum uric acid level and urea nitrogen level in the mice significantly increased ( P < 0. 01) in the group with 1?day combination medication of hypoxanthine and oteracil potassium, the renal tubular type was abundantly observed in renal cortex, and salt crystals were abundantly observed in renal medulla. The serum uric acid level and urea nitrogen level in the mice increased significantly ( P < 0. 01), and liver XOD activity decreased ( P < 0. 05) in the group with 7?day combination medication of hypoxanthine, ethambutol, and oteracil potassium, and eosinophilic insoluble proteins were found in some of the proximal tubules of the renal cortex. The serum uric acid level, urea nitrogen level, and creatinine level in the mice significantly increased ( P < 0. 01) in the group with 14?day combined medication of yeast extract and oteracil potassium and the group with 14?day combined medication of yeast extract, adenine, and oteracil potassium. Renal tubular epithelial cells fell off in the renal cortex, and eosinophilic insoluble proteins were visible in some of the proximal tubules of the mice in the group with combined medication of yeast extract and oteracil potassium. Salt crystals were abundantly observed in the renal medulla of the mice in the group with combined medication of yeast extract, adenine, and oteracil potassium. The body weight of the yeast extract and oteracil potassium group increased faster than that of the yeast extract, adenine, and oteracil potassium group, with a significant difference between their body weights ( P < 0. 05). Conclusions Compared with other modeling method , the mouse model with hyperuricemic renal damage induced by the combined medication of yeast extract and oteracil potassium was more stable and its establishment had no significant effect on the body weight of the mice. Therefore, it is more suitable to use yeast extract combined with oteracil potassium once a day for 14 days to establish a mouse model of hyperuricemia renal damage.