The present study was conducted to explore the toxic effects of lead (Pb) on the physiological responses of Japanese quails and to investigate the potential modulatory role of Yucca schidigera extract (YSE) against these effects. 360 mature Japanese quails (at 2 months of age) were used and the experiment was lasted for 8 weeks. The birds were divided into six equal groups as follow: control (basal diet, BD), BD+Pb (100 mg/kg diet), BD +YSE (100 mg/kg diet), BD+YSE (200 mg/kg diet), BD+Pb (100 mg/kg diet) +YSE (100 mg/kg diet) and BD +Pb (100 mg/kg diet) +YSE (200 mg/kg diet). Pb induced a significant reduction in superoxide dismutase (SOD) and catalase (CAT) activities and reduced glutathione (GSH) level. While, increased protein carbonyl (PC) and malondialdehyde (MDA) content in tissues of exposed birds. Pb increased level of 8-hydroxy-2-deoxyguanosine (8-OHdG) and lactate dehydrogenase (LDH) activity in serum. YSE significantly reduced the Pb -induced oxidative stress in co-treated groups especially at 200 mg/kg diet. YSE could modulate the Pb –induced decreased urea, creatinine and beta-2 microglobulin (B2M) levels. YSE200 was found to be better than the YSE100 in decreasing levels of inflammatory markers including tumor necrosis factor (TNF-α), nitric oxide (NO), transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF). Furthermore, YSE significantly regulates glucose homeostasis in co-exposed quails. Pb residues were found to be significantly higher in kidney and pancreas tissues of Pb group compared to other groups. YES decreased the expression of metallothionein-1 in the renal and pancreatic tissues, while elevated insulin expression in the pancreatic cells by immunostaining in co-exposed groups. In conclusion, the present results conclusively demonstrate the potential modulatory effect of YSE against the Pb-induced toxic effects in different organs of Japanese quails.