Reuse of wastewater through a combination of advanced wastewater treatment (AWT) and managed aquifer recharge (MAR) is an important water management option. As an integral part of any AWT-MAR system, the geochemical compatibility of the recharged water with the targeted aquifer must be assessed to avoid groundwater quality deterioration. Although short-term field experiments may uncover potentially concerning sediment-water disequilibria, an advanced analysis is often required to understand the long-term geochemical impacts of large-scale MAR. Here, we develop and apply a pragmatic approach to upscale and verify the previously derived local-scale geochemical understanding to the spatial and temporal scale required for assessing and managing large-scale and long-term impacts resulting from the recharge of AWT-processed water. We use Australia's largest MAR scheme, in which aerobic, purified water is injected into deep, anaerobic, pyritic aquifers as an illustrative example. In this case, the local-scale understanding was derived from a comprehensive field trial and the interpretation of the data through a trial-scale high-resolution reactive transport model (RTM). Based on (i) the trial-scale RTM, (ii) new data from the early phase of the full-scale MAR, and (iii) downscaling of an existing, regional-scale flow model, we developed an upscaled RTM to assess two critical issues for the large-scale groundwater replenishment of Perth deep aquifers, that is, the sustainability of native pH buffering processes and the dynamics of fluoride release and attenuation. In a final step we illustrate how the upscaled RTM can be applied to assess how changes in the AWT affect long-term groundwater pH changes.