Objective To investigate the effect and mechanism of 4-octyl itaconate（4-OI） in alleviating early renal injury induced by high-fat diet（HFD） via the nuclear factor erythroid 2-related factor 2（Nrf2）/antioxidant response element（ARE） pathway. Methods Mice were randomly divided into control group，HFD group，and 4-OI group. The mice in the HFD group and the 4-OI group were given HFD feeding for 12 weeks，and those in the 4-OI group were given 4-OI intervention since week 9 of HFD feeding. Glucose tolerance and urinary albumin-to-creatinine ratio（UACR） were measured；HE staining and periodic acid-Schiff staining were used to observe the pathological changes of renal cortex；ELISA was used to measure blood lipids and renal cortical oxidative stress-related indicators；the expression levels of renal tubular injury markers and the molecules involved in the Nrf2/ARE pathway in renal cortex were measured. Results This study showed that 4-OI intervention significantly alleviated the brush border fracture and epithelial cell shedding of renal proximal convoluted tubules and reduced the expression levels of the renal tubular injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in renal cortex and the content of UACR in urine supernatant（P=0.001，0.002，and 0.000），and it also reduced renal cortical oxidative stress，including the increases in glutathione and superoxide dismutase（SOD） and the reduction in malondialdehyde（P=0.040，0.000，and 0.001）. 4-OI intervention increased the protein and mRNA expression levels of Nrf2 and the Nrf2/ARE pathway-related molecules heme oxygenase-1，NAD（P）H dehydrogenase［quinone］1，and superoxide dismutase 1（protein expression：P=0.003，0.000，0.001，and 0.000； mRNA expression：P=0.000，0.009，0.000，and 0.000）. Conclusion 4-OI may reduce the level of renal oxidative stress by activating the Nrf2/ARE pathway，thereby improving early renal injury caused by HFD.