Radionuclide migration in clay-rich formations is typically dominated by diffusion considering the low permeability of these formations. An accurate estimation of radionuclide migration in host rocks using numerical tools plays a key role in the safety assessment of disposal concepts for nuclear waste. In the sandy facies of the Opalinus Clay (SF-OPA), the spatial variability of the pore space network and compositional heterogeneity at the pore scale (nm to μm) cause heterogeneous diffusion at the core scale (cm to dm). Such heterogeneous diffusion patterns affect the migration of radionuclides in various sedimentary layers even above the core scale (m). In this work, we study the heterogeneous diffusion of cations based on a two-dimensional (2D) structural model at the m-scale. As key parameters for the diffusive transport calculation, the effective diffusion coefficients in different sedimentary layers are quantified based on our previous developed up-scaling workflow from pore- to core-scale simulation combined with the multi-scale digital rock models. The heterogeneous effective diffusivities are then implemented into the large-scale structural model for diffusive transport simulation using the FEM-based OpenGeoSys-6 simulator. The sensitivity analysis focuses on the effects of the SF-OPA bedding angle and the effect of different layer-succession layout with different canister emplacement on the spatio-temporal evolution of radionuclide diffusion front line. Results show that the moving distance of the diffusion front is farther away from the canister center, along the direction with the neighboring layer having lower diffusion coefficient within the total simulation time of 2000 years. When the bedding angle increases, the diffusion front moves farther in in vertical upward direction direction, which has less retardation effect for the radionuclide from the ground surface point. For different layer-succession layout with different canister emplacement, the smallest migration distance of the diffusion front line is 1.65gm. Within 2000 years, for the conceptual model 2B that the canister is emplaced in the layer with the highest diffusivity coefficient, the diffusion front can migrate 0.19gm farther along vertical downward direction due to the influence of the neighboring layer. The numerical results provide insight into the effects of rocks heterogeneity on diffusion of radionuclides, contributing to enhanced long-term predictability of radionuclide migration in SF-OPA as potential host rock for a deep geological repository.