Excessive fructose (FRU) intake can result in insulin resistance and metabolic disorder, which are related to renal injury.18α-Glycyrrhetinic acid (GA) is a bioactive component mainly extracted from Glycyrrhiza radix, and has anti-oxidant and anti-inflammatory activities. However, its effects on FRU-induced renal injury still remain unclear. In this study, we found that 18α-GA treatments could significantly ameliorate the cell viability in FRU-treated tubule epithelial cells, accompanied with improved mitochondrial membrane potential. Furthermore, reactive oxygen species (ROS) accumulation in FRU-stimulated cells was markedly reduced by 18α-GA, which were associated with the activation of nuclear factor (erythroid-derived-2)-like 2 (Nrf-2) and the blockage of MAPKs signaling. Additionally, dyslipidemia detected in FRU-treated cells was greatly inhibited by 18α-GA. We also found that 18α-GA significantly ameliorated FRU-induced inflammation in cells through reducing the expression of pro-inflammatory cytokines and chemokine. The anti-inflammatory effects regulated by 18α-GA were mainly related to the repression of nuclear factor-κB(NF-κB) signaling. Furthermore, the protective effects of 18α-GA against ROS production, lipid accumulation and inflammation were verified in renal tissues from FRU-challenged mice, consequently improving metabolic disorder and kidney injury. Taken together, these findings demonstrated that 18α-GA exerted renal protective effects through reducing oxidative stress, lipid deposition and inflammatory response, and thus could be considered as a promising therapeutic strategy for metabolic stress-induced kidney injury.