Abstract: Objective To investigate the effect of empagliflozin on oxidative stress in type 2 diabetic kidney disease (DKD) and its possible mechanism. Methods In the current study, db/db mice were used as a rodent model of DKD and randomly divided into two groups: a model (DM) group and an empagliflozin (DM+EM) group, while db/m mice were used as a normal control (NC) group. Their body weight and fasting blood glucose were recorded. After 8 weeks of continuous administration, blood and urinary samples were collected to measure creatinine (Cr), urea nitrogen (BUN) and urinary microalbumin (mALB). Meanwhile, renal tissue homogenate was used to detect renal oxidative stress parameters. Masson staining was used to observe the changes of renal fibrosis. qRT-PCR was used to detected the mRNA levels of NF-E2 related factor (Nrf2), quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Western blot was used to detect the protein expression of Nrf2, NQO1 and HO-1. Results Compared with the NC group, the DM group showed significant increases in body weight and blood glucose, Cr, BUN and mALB, decreases in SOD activity and GSH content, increases in MDA content, increased deposition of collagen fibers in renal tissue, and decreased expression of nuclear Nrf2, NQO1 and HO-1(P＜0.05 or P＜0.01). Compared with the DM group, the DM+EM group presented significant decreases in blood glucose, Cr and mALB contents, increases in SOD activity and GSH content, relieved renal fibrosis, and significantly increased expression of total Nrf2, nuclear Nrf2, NQO1 and HO-1(P＜0.05 or P＜0.01). Conclusions Empagliflozin can reduce the level of oxidative stress in renal tissue of diabetic mice by activation of the Nrf2 pathway and up-regulation of NQO1 and HO-1 protein expression.