Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown. This study aims to evaluate the therapeutic effect of phloretin on HUA-induced renal injury in mice and to reveal its underlying mechanism. Mice were induced hyperuricemic by oral gavage of adenine/potassium oxonate. The effects of phloretin on renal function, fibrosis, oxidative stress, inflammation, and UA metabolism in HUA mice were evaluated. The effect of phloretin on NLRP3 pathway was analyzed in human renal tubular cell lines (HK-2). HUA mice showed renal dysfunction with increased renal fibrosis, inflammation and mitochondrial stress. By contrast, phloretin reduced the level of serum blood urea nitrogen (BUN), urinary albumin to creatinine ratio (UACR), tubular necrosis, extracellular matrix (ECM) deposition and interstitial fibroblasts in HUA mice. The renal infiltration of inflammatory cells, cytokines such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1β (IL-1β) release, mitochondrial reactive oxygen species (ROS) and morphological lesions in HUA mice also decreased. Furthermore, phloretin partly inhibited renal glucose transporter 9 (GLUT9) and promoted urinary UA excretion in HUA mice. In vitro, phloretin suppressed the NLPR3 pathway under LPS or UA stimulation in HK-2 cells. Phloretin could effectively attenuate UA-induced renal injury via co-inhibiting NLRP3 and UA reabsorption, and thus it might be a potential therapy to hyperuricemia-related renal diseases. Copyright © 2019 Elsevier GmbH. All rights reserved.