Faults may impact regional groundwater flow and transport, so it is important to include them during aquifer-system conceptualization and while constructing groundwater flow models. For the Neogene aquifer in Flanders (Belgium), three-dimensional groundwater-flow and solute-transport models have been developed in the framework of safety and feasibility studies for the underlying Boom Clay Formation as a potential host for geological disposal of radioactive waste. The model outcomes are subject to uncertainties as they are typically constrained only by hydraulic heads, and their current conceptualization does not differentiate the fault zones from the undisturbed hydrostratigraphic formations. A groundwater flow model has been developed using MODFLOW-2005 to investigate how groundwater flow in the sedimentary Neogene aquifer may be disturbed by the Rauw Fault—a 55-km-long normal fault—across the Nete catchment. The observed hydraulic gradient across the fault zone appears significant, with head differences of 1.5–2.0 m over a horizontal distance of 60 m. A simulated hydraulic-head difference of 2.4 m was achieved largely corresponding to the observed behavior. The Neogene aquifer, within the Nete catchment, seems to be composed of several local flow systems and potentially with a deeper more semiregional/intermediate flow system. Testing different fault configurations shows the impact on the local/semiregional flow system, with pronounced effects in the fault’s vicinity, and extending or narrowing the flow systems further away. These results demonstrate the importance of considering faults, or any other hydrogeological subsurface barrier/conduit, and suggests they should be accounted for in the general practice of subsurface activity impact assessment.