In large aquifers relevant for their considerable size, regional groundwater modeling remains challenging given geologic complexity and data scarcity in space and time. The Guaraní Aquifer System is the largest transboundary aquifer in South America. It contains an enormous volume of water, however, it is not well known being difficult to assess the impact of exploitation currently used to supply over 25 million inhabitants. This is a sensitive issue because the aquifer is shared by four countries. Moreover, an integrated groundwater model, and therefore, a global water balance were not available. In this work, a transient regional scale model for the entire aquifer based upon five simplified, equally plausible conceptual models represented by different hydraulic conductivity parametrizations, is used to analyze the flow system and water balance components. Combining an increasing number of hydraulic conductivity zones and an appropriate set of boundary conditions, the hypothesis of a continuous sedimentary unit yielded errors within the calibration target in a regional sense. The magnitude of the water budget terms resulted very similar for all parametrizations. Recharge and stream/aquifer fluxes were the dominant components representing, on average, 84.2% of total inflows and 61.4% of total outflows, respectively. However, leakage was small compared to stream discharges of main rivers. For instance, the simulated average leakage for the Uruguay river was 8 m<sup>3</sup> s<sup>−1</sup> while the observed absolute minimum discharge was 382 m<sup>3</sup> s<sup>−1</sup>. Streams located in heavily pumped regions switched from a gaining condition on early years to a losing condition over time. Water is discharged through the aquifer boundaries, except at the eastern boundary. On average, pumping represented 16.2% of inflows while aquifer storage experienced a small overall increment. The model water balance indicates that the current rate of groundwater withdrawals does not exceed the rate of recharge on a regional sense.