Hereditary renal hypouricemia type-1 (RHUC1) is a rare disease associated with markedly lower plasma urate (UA) and increased fractional excretion of UA (FE_UA) due to URAT1 dysfunction, and exercise-induced acute kidney injury (EIAKI) is known to be a serious complication, but its pathogenesis is unknown. The aim of this study is the investigation of pathogenesis of EIAKI and the effect of topiroxostat, a non-purine-type xanthine oxidoreductase inhibitor (XOI) using high HPRT activity Urat1-Uox double knockout (DKO) mice establishing as novel animal model of RHUC1. DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. In DKO mice, exercise exacerbated renal injury and functional markers, and increased urinary UA/Cr ratio and plasma UA. In addition, NLPR3 inflammasome activation and increased IL-1β were observed in the kidney. Finally, we demonstrated that topiroxostat improved renal injury and functional parameters of EIAKI. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1β via NLRP3 inflammasome signaling associated with excessive urinary UA excretion. In addition, topiroxostat, a non-purine-type XOI, appears to be a promising therapeutic agent for the treatment of EIAKI.