The mesostructure (millimeter to micrometer scale) of clay‐rich sedimentary rocks is generally characterized by a connected fine‐grained clay matrix embedding coarser nonclay minerals. We use the Callovo‐Oxfordian clay‐rich rock formation (France) to illustrate how mesostructure influences solute transfer in clay‐rich rocks at larger scales. Using micrometer resolution imaging techniques (SEM and micro‐CT) major mineral phases (clay matrix, carbonates, tectosilicates, and heavy minerals) were mapped both in two dimensional (2‐D) and three dimensional (3‐D) at the mesoscale. Orientation and elongation distributions of carbonate and tectosilicate grains measured on mineral maps reveal an anisotropic mesostructure relative to the bedding plane, in agreement with the geological history of the sedimentary rock. Diffusion simulations were performed based on the 3‐D mineral maps using a random walk method thus allowing direct computation of mesoscopic scale‐related diffusion anisotropy and tortuosity. Considering an isotropic clay matrix, simulated diffusion anisotropy (1.11–1.26) was found lower than the one experimentally measured on macroscopic samples (1.5 to 2), due to the anisotropy feature of pores within the clay matrix. The effects of the mineral content variations on diffusion properties were then investigated by numerical modifications of a mineral map combined with diffusion simulations. Evolution of the tortuosity and diffusion anisotropy with the clay matrix content were successfully interpreted by the Koponen percolation/diffusion model, whereas the Archie approach fails to reproduce diffusion properties at low clay contents. A comparison of fitting parameters with those obtained experimentally indicates that diffusion coefficient variations observed at a large scale could be mainly controlled by the mesostructure. The 3D mesoscale struture of the Callovo‐Oxfordian formation was imaged Carbonate and tectosilicate arrangements influence the diffusion properties In clay rocks, Archie's law can be related to changes in mineral contents