Diffusion is an important (or the dominant) mass transport mechanism for transfer of water-soluble solutes between adjacent sandstones and mudstones during the mesodiagenetic stage. Numerical simulations of water–rock interactions with constraints of diffusion were conducted in three different types of interbedded mudstone–sandstone (MS) systems. Results suggest that diffusive transfer varies significantly for different solutes. In a simple MS system, K+ and Ca2+ released by mineral reactions can diffuse on the meter scale, across the interface between the sandstone and mudstone, driven by significant concentration gradients of the solutes. A marginal cemented sandstone layer between porous sandstone and mudstone in a here-called MS-C system retards the diffusive transfer of K+ and Ca2+ significantly. An open fracture in an MS fracture crossing system promotes the diffusive transfer of K+ and Ca2+ in zones close to it. The diffusive transfer of SiO2(aq) and Al3+ is much slower than K+ and Ca2+ in all the three systems, particularly for aluminum ion with extremely low concentration. Because the diffusion processes of the solutes are scale-limited, internal K+ sources are needed for illitization reactions in thick mudstones, and internal SiO2(aq) sources are needed for quartz cementation in sandstones. Due to the simultaneous in situ precipitation of secondary clay and quartz minerals following mineral dissolution, secondary pores generated during the mesodiagenetic stage are redistributional pores. Multiscale diffusive mass transfers link mineral reactions at different scales. Meter-scale diffusion of K+ across the mudstone–sandstone interface simultaneously promotes feldspar alteration and quartz cementation in the marginal part of the sandstone and also promotes illitization of clays in the marginal part of the mudstone. Microscale diffusion of K+ released by leached K-feldspars in the mudstone itself likely promotes illitization in the central part of the mudstone. The illitization reaction, in turn, promotes additional feldspar dissolution in the central mudstone. Overall, the diffusive transfers of various water-soluble solutes, via coupling of different mineral reactions, lead to continuous diagenetic reactions in hydrous geochemical systems with different minerals. These processes make the subsurface primary homogeneous sandstone and mudstone rocks more and more heterogeneous. Such heterogeneity (e.g., more quartz cements in marginal sandstones), a natural result following heterogeneous mineral alterations, cannot be used directly as evidence to support large-scale transfer of the solutes with low concentrations.