Quercetin (QE), the major bioflavonoid in the human diet, has been reported to have many benefits and medicinal properties. However, its protective effects against lead (Pb)-induced neurotoxicity have not been clarified. The aim of the present study was to investigate the effects of QE on neurotoxicity in mice exposed to Pb. Mice were exposed to lead acetate (20 mg/kg body weight/day) intragastrically with or without QE (15 and 30 mg/kg body weight/day) coadministration for 3 months. The data showed that QE significantly prevented Pb-induced neurotoxicity in a dose-dependent manner. Exploration of the underlying mechanisms of QE action revealed that QE administration decreased Pb contents in blood (13.2, 19.1%) and brain (17.1, 20.0%). QE markedly increased NO production (39.1, 61.1%) and PKA activity (51.0, 57.8%) in brains of Pb-treated mice. Additionally, QE remarkably suppressed Pb-induced oxidative stress in mouse brain. Western blot analysis showed that QE increased the phosphorylations of Akt, CaMKII nNOS, eNOS, and CREB in brains of Pb-treated mice. The results suggest that QE can inhibit Pb-induced neurotoxicity and partly restore PKA, Akt, NOS, CaMKII, and CREB activities.