Lead is one of the most common heavy metal pollutants in the environment. Prolonged exposure to lead will induce oxidative stress, inflammation, and apoptosis in the kidneys, which in turn causes kidney injury. Lycium barbarum polysaccharide (LBP) is well known for its numerous pharmacological properties. This study aims to explore the efficacy and mechanism of LBP against lead-induced kidney damage in mice. Symptoms of renal injury were induced in mice by using 25 mg/kg lead acetate (PbAc2), and different doses of LBP (200, 400, and 600 mg/kg BW) were orally administrated to PbAc2-treated mice for five weeks. The results of the pharmacodynamics experiment showed that the renal pathological damages, serum creatinine (Cre), blood urea nitrogen (BUN), and kidney index of PbAc2-treated mice could be significantly alleviated by treatment with LBP. Further, LBP treatment significantly increased the weight and feed intake of PbAc2-treated mice. The dose effect results indicated that a medium dose of LBP was superior to high and low doses. The results of mechanistic experiments showed that LBP could attenuate oxidative stress, inflammation, and apoptosis in the kidneys of mice with lead toxicity by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.