Wheat faces escalating vulnerability to heat stress as a consequence of climate change, resulting in a substantial annual loss of up to 30% in global wheat productivity. Nanotechnology emerges as a promising frontier, with the potential to revolutionize agriculture across various stages, from seed priming to post-harvest storage. In this study, biogenic zinc oxide nanoparticles (ZnO-NPs) synthesized from Lantana camara leaf extracts was evaluated on growth, morphological, bio physiochemical and molecular parameters in four wheat genotypes. The application of ZnO-NPs, particularly at a concentration of 100 ppm, significantly improved various seed growth parameters and total protein content. Genetic analyses unveiled substantial variability among wheat genotypes under both non-stress and heat-stress conditions. Heritability and genetic advance estimates underscored spike length and grain yield as promising traits. Moreover, genotypic and phenotypic correlations revealed intricate relationships between agronomic traits, providing valuable insights for targeted breeding strategies. Path analysis elucidated the direct and indirect contributions of traits to grain yield, emphasizing the significance of biomass, effective tillers per plant, and spike length. Physiological and biochemical responses indicated that ZnO-NPs alleviated the adverse effects of heat stress on chlorophyll content, photosynthetic rate, relative water content, and cellular membrane stability. Simultaneously, ZnO-NPs enhanced proline, catalase, peroxidase and superoxide dismutase activities. Gene expression analysis of heat shock proteins (HSP17, Hsp23, and Hsp70) in heat-tolerant and heat-sensitive genotypes under various heat shock treatments revealed distinct responses, with HSP17 exhibiting the highest expression in PBW226 under stress conditions. Overall, this research showcases the potential of biogenic ZnO-NPs to enhance wheat resilience in the face of climate change, highlighting nanotechnology's pivotal role in modern agriculture and its contribution to global food security.