Background <p>Lead (Pb) pollution is a severe environmental condition that inhibits the growth of plants by causing oxidative stress and interference with cellular and molecular functions. Genotypic variation in stress tolerance has been identified in wheat varieties (<i>Triticum aestivum</i> L.), but there has been limited evidence of integrated physiological, biochemical, and transcriptomic responses to Pb.</p> Results <p>Pb exposure (0–3 mM lead acetate) had significant effect on shoot height and root length in all wheat varieties with root being more sensitive than shoot. The BARI Gom 30 genotype variety showed a relatively higher tolerance with BARI Gom 25 being the most sensitive. The markers of oxidative stress (H₂O₂ and MDA) were increased in a dose-dependent manner, which indicates enhanced cellular damage under Pb stress. The initial increase in antioxidant enzymes (CAT, POD, and APX) occurred at moderate intensity and declined at high concentrations, indicating that defense capacity is broken down at high levels of stress. Transcriptomic analysis of wheat root tissues (GEO accession: GSE235844) identified differentially expressed genes that were related to regulation of oxidative stress, ion transport, protein degradation, and transcriptional control. These molecular responses were correlated with observed physiological and biochemical alterations, which indicate well-coordinated mechanisms of stress-responses. Dataset integration revealed the important pathways that are involved in redox balance and stress adaptation.</p> Conclusion <p>The physiological, biochemical, and molecular responses involved in Pb toxicity in wheat are interconnected with each other. Genotypic differences in tolerance highlight the importance of genetic factors in stress adaptation. This integrative analysis provides mechanistic insights into Pb stress responses and supports future breeding of heavy metal–tolerant wheat varieties.</p>