Accurate modeling and simulation of radionuclide migration in clay rocks such as the Opalinus Clay play a key role in the safety assessment of deep geological repositories for nuclear wastes. At the continuum scale, the representative elementary volume (REV) is a fundamental constraint to quantify the effective diffusivity, which is a key parameter in reactive transport (RT) models. Therefore, an accurate estimation of the REV is essential for a meaningful continuum-scale RT simulation in heterogeneous clay rocks. This study presents a comprehensive analysis of the heterogeneities of porosity and effective diffusivity in clay rocks by using the classical sampling theory and pore-scale simulations. First, in this study, the two-dimensional representative elementary area (REA) is correlated with the REV for porosity via a characteristic length. Next, it is shown that the REV for diffusivity is larger than the REV for porosity. Moreover, these two REVs can be correlated using Archie’s law. In such a way, the REV for diffusivity can be determined by the developed correlations through analyzing two-dimensional microstructures, thus significantly reducing the computational cost. Finally, the applicability of our approach for clay rocks is validated by experimental data on the diffusion of tritiated water in the heterogeneous sandy facies of Opalinus Clay. From both the experimental data and the modeling prediction, the REV for diffusivity in the sandy facies of Opalinus Clay is in the order of cubic centimeters. This study provides critical insights into the diffusion in heterogeneous clay rocks towards an enhanced predictability of radionuclide migration.