The stable isotopes 2H and 18O, combined with noble gases and radioisotopes (e.g., 3H, 14C, 36Cl), are used to infer groundwater age and climate during recharge. Flow regimes within low-velocity flowpaths and long residence times could allow an aquitard-aquifer diffusive flux to alter isotope abundance. Consequently, the diffusion of isotopes (e.g., 14C, 2H and 18O) between aquifers and confining layers needs to be considered in such conditions. In this study, COMSOL Multiphysics was used to determine if diffusion of 18O (and 2H by proxy) from a bounding aquitard could explain observed downgradient enrichment of 2H and 18O within a regional aquifer. Using the geologic and hydraulic properties of the lower Wilcox aquifer of the Mississippi Embayment aquifer system in Missouri and Arkansas, the advection-dispersion equation was solved along a 1-D groundwater flow domain, coupled with a cross-contact aquitard-aquifer diffusive flux. Although the observed signal within the lower Wilcox was not matched, a sensitivity analysis indicated the importance of the isotope composition gradient between the aquifer and aquitard. Furthermore, groundwater velocity was suggested as a controlling influence on aquitard-aquifer exchange that could alter aquifer isotope composition.