The present study explored the neurotoxic impacts of lead (Pb) and the potential alleviating effect of Yucca schidigera extract (YSE) in Japanese quails. About 360 adult Japanese quails (8 weeks old) were used. Quails were randomly distributed to six groups with 4 replicates each: the control group (fed basal diet, BD), the BD + YSE1 and BD + YSE2 groups (BD + 100 and 200 mg/kg diet of YSE, respectively), the Pb group (BD + 100 mg/kg Pb), and the Pb + YSE1 and Pb + YSE2 groups (BD + Pb + 100 and 200 mg/kg YSE, respectively). This feeding trial lasted for 8 weeks. The exposure to Pb in the diet induced oxidative damage stress in the brain of exposed quails reflected by the significant increase in the oxidative markers including malonaldehyde (MDA) and protein carbonyl (PC) and the significant reduction in the activities of antioxidants including catalase (CAT), superoxide dismutase (SOD), and the reduced glutathione (GSH). Brain neurochemistry and enzyme activities were also altered following Pb exposure. Pb significantly reduced serotonin, dopamine, norepinephrine, GABA, Ach, and Na + /K + -ATPase activities. Pb dietary intoxication markedly increased brain inflammatory biomarkers, including tumor necrosis factor (TNF-α), myeloperoxidase, and nitric oxide. Peripherally, Pb toxicity decreased the amino acid neurotransmitters (glutamic acid, glycine, and aspartic acid) in the serum of birds. At the transcriptomic level, Pb exposure upregulated the transcription patterns of CASP3, TNF-α, HSP70, and IL-1β. The single effect of YSE maintained that all the assessed parameters were not changed compared to the control. Interestingly, the YSE co-supplementation with Pb alleviated the Pb-induced neuro-oxidative damages by lowering the lipid, protein, and DNA damage, and the inflammatory biomarkers.