Objective In this experiment, a mouse model of nephropathy induced by lead acetate was created tostudy the mechanism of detoxification and protection of grub peptide extract on mice, which provided experimental evidencefor the prevention and treatment of lead-induced nephropathy. Methods Mice were randomly divided into a Control group,Model group, Positive drug group, and Grub peptide groups. The Grub peptide groups were given different doses (80,160, 320 mg/ kg) of grub peptide. All mice, except the Control group, were injected intraperitoneally with 20 mg/ kg leadacetate every other day, for 15 consecutive days. The mice in the Control group and Model group were then fed normalsaline, while the mice in the Positive drug group were fed a dimercaptosuccinic acid (DMSA 70 mg/ kg) suspension. Themice in the Grub peptide groups were fed different doses of grub peptide extract. The state of the kidney tissue was observedby HE staining once a day for 15 days. The renal function indexes (BUN, Cr), antioxidant enzyme levels (SOD, GSHPx),and peroxide (MDA) content in renal tissue were detected. RT-PCR and Western Blot techniques were used todetect and analyze the gene and protein expression levels of phase II detoxification enzyme (NQO1), an antioxidant enzyme(HO-1), and a signaling molecule (Nrf2). Results The weight of mice in the Grub peptide groups was greater than thosein the Model group; however, they were less than those in the Control group, and the morphology of the kidney tissue wassignificantly better. Compared with the control group, the morphology of the kidney tissue of mice in the Grub peptidegroups was significantly improved, the level of BUN and Cr in the serum was significantly less ( P < 0. 05), the level ofantioxidant enzymes (SOD, GSH-Px) in renal tissue was significantly less ( P < 0. 05), and the content of MDA wassignificantly less. The phase II detoxification enzyme gene (NQO1), antioxidant enzyme (HO-1), and signal molecule(Nrf2) mRNA, and protein expression levels were significantly up-regulated ( P < 0. 01). Conclusions Grub peptidescan activate Nrf2-ARE signaling pathway to enhance antioxidant function and increase the gene expression of detoxificationenzymes in lead-poisoned mice. The protective detoxification effect can then be extracted.