Lead (Pb) contamination is a critical environmental issue that poses a substantial threat to agricultural sustainability and crop productivity, particularly for staple crops like wheat (Triticum aestivum L.). This study investigates the differential physiological, biochemical, and anatomical responses of two wheat cultivars, SKD-1 and Borlaug-16, under Pb stress (100 mg/kg Pb for 21 days). Borlaug-16 displayed a notable tolerance to Pb toxicity, evidenced by a significant increase in total biomass, including a 41.22% rise in shoot turgid weight and a 23.37% increase in root turgid weight, alongside a 57.72% enhancement in root cortex thickness. This cultivar also showed increased antioxidant enzyme activities, such as catalase and peroxidase, and a better ionomic balance, maintaining higher levels of essential minerals like Ca in leaf tissues while effectively accumulating Pb and other trace elements in roots. In contrast, SKD-1 suffered from a more substantial reduction in essential minerals and weaker anatomical and biochemical defenses. The study's novelty lies in providing an integrated approach to understanding wheat cultivar-specific adaptations to Pb stress, suggesting Borlaug-16 as a promising candidate for cultivation in Pb-contaminated soils. These findings underscore the importance of developing Pb-tolerant cultivars to ensure sustainable wheat production in polluted environments.