Iron (Fe) and phosphate (P) are essential mineral nutrients for plant growth and development. While it is known that Fe and P pathways interacts within plants however, our understanding of the molecular mechanisms regulating nutrient interaction during plant vegetative and reproductive stages remains largely unknown. Herein, we provide a comprehensive physiological and molecular analysis of hexaploid wheat response to single P/Fe and combined Fe and P deficiency. Our data showed that wheat primary root growth was inhibited in response to –Fe, and remarkably rescued by co-occurring deficiencies of Fe and P. Transcriptome analysis revealed drastic and distinct molecular rearrangements to adapt the single and combined nutrient stress with dominance of Fe responsive cis-regulatory elements. Gene-based clustering and root-specific transcriptome expression analysis identify several important unique components induced in response to combined stress –Fe–P, including UDP glycosyltransferases and cytochrome-P450 and glutathione metabolism. These data are consistent with our metabolome data, which further reveals specific metabolite accumulation in –Fe–P those include amino-isobutyric acid, arabinonic acid and aconitic acid. Finally, at reproductive stage alleviations of the negative effect of Fe was also observed in –Fe–P (i.e. spikelet and grain development). Collectively, the data obtained is essential for designing new strategies to improve resilience of crops to cope with the limited nutrients in soils.