Enhancing photosynthesis is widely accepted as critical to advancing crop yield. However, yield consequences of photosynthetic manipulation are confounded by feedback effects arising from interactions with crop growth, development dynamics and the prevailing environment. Here, we developed a cross-scale modelling capability that connects leaf photosynthesis to crop yield in a manner that addresses the confounding factors. The model was validated using data on crop biomass and yield for wheat and sorghum from diverse field experiments. Consequences for yield were simulated for major photosynthetic enhancement targets related to leaf CO2 and light energy capture efficiencies, and for combinations of these targets. Predicted impacts showed marked variation and were dependent on the photosynthetic enhancement, crop type and environment, especially the degree of water limitation. The importance of interdependencies operating across scales of biological organization was highlighted, as was the need to increase understanding and modelling of the photosynthesis-stomatal conductance link to better quantify impacts of enhancing photosynthesis.