While the general effect of CO2 enrichment on photosynthesis, stomatal conductance, nitrogen elemental content or yield has been documented, there is still some uncertainty as to whether there are interactive effects between CO2 enrichment and other factors (such as temperature, geographical location, water availability and cultivar). In addition, the metabolic coordination between leaves and grains, which is crucial for crop responsiveness to elevated CO2, has never been examined closely. Here, we addressed these two aspects by taking advantage of several FACE experiments across five different countries using multi-level analyses. There was little effect of elevated CO2 on yield (except in USA) likely due to photosynthetic capacity acclimation, as reflected by protein profiles. Also, there was a significant decrease in leaf amino acids (threonine) and macro-elements (such as K) at elevated CO2, while other elements such as magnesium (Mg) or sulfur (S) increased. Despite the insignificant effect of CO2-enrichment on yield, grains appeared to be significantly depleted (as expected) in N, but also in threonine, the S-containing amino acid methionine and Mg. Overall, our results suggest a strong detrimental effect of CO2 enrichment on nutrient availability and remobilization from leaves to grains.