Maintaining high rates of photosynthesis in leaves requires efficient move- ment of CO2 from the atmosphere to the mesophyll cells inside the leaf where CO2 is converted into sugar. CO2 diffusion inside the leaf depends directly on the structure of the mesophyll cells and their surrounding air- space, which have been difficult to characterize because of their inherently three-dimensional organization. Yet faster CO2 diffusion inside the leaf was probably critical in elevating rates of photosynthesis that occurred among angiosperm lineages. Here we characterize the three-dimensional surface area of the leaf mesophyll across vascular plants. We show that genome size determines the sizes and packing densities of cells in all leaf tis- sues and that smaller cells enable more mesophyll surface area to be packed into the leaf volume, facilitating higher CO2 diffusion. Measurements and modelling revealed that the spongy mesophyll layer better facilitates gas- eous phase diffusion while the palisade mesophyll layer better facilitates liquid-phase diffusion. Our results demonstrate that genome downsizing among the angiosperms was critical to restructuring the entire pathway of CO2 diffusion into and through the leaf, maintaining high rates of CO2 supply to the leaf mesophyll despite declining atmospheric CO2 levels during the Cretaceous.